6th Annual Science and Standards SymposiumJanuary 16, 2013Istanbul

Determination of Solubility and Permeability in BCS

Erika Stippler, Ph.D.DirectorDosage Form Performance Laboratory

BCS Concept

Published by Amidon and co-workers 1995

Biopharmaceutics Classification System is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

The aim is to optimize the development of oral dosage forms relying only on rate limiting factors for absorption

Drug Release – The Rate Limiting Step

Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

Class Solubility Permeability I High High II Low HighIII High Low IV Low Low

Solubility directly influences the dissolution behavior of oral dosage forms in gastrointestinal tract

Biopharmaceutical Drug Classification System (BCS)

BCS Solubility: FDA vs. EMA

FDA

– Solubility profile in the range of pH 1- 7.5 at 37 ± 1 °C

– At least 3 buffers

– At pH=pKa, pH=pKa-1, pH=pKa+1 (where applicable)

– USP buffers

– Minimum of 3 replicates

EMA

– Solubility profile in the range of pH 1- 6.8 at 37 ± 1 °C

– At least 3 buffers (1.2, 4.5, 6.8)

– At pH=pKa (where applicable)

– Buffers not specified (PhEur)

– Sufficient number of replicates

Solubility Determination

Equilibrium solubility (thermodynamic solubility)

– Drug dissolved is in equilibrium with solid remaining on the bottom.

Kinetic solubility (turbidimetric solubility)

– Solubility at time point X. Precipitate present but equilibrium not necessarily reached. Supersaturation and subsaturation possible.

Intrinsic solubility

– Equilibrium solubility of the free acid or base form of an ionizable compound at a pH where it is fully de-ionized.

Solubility Determination: Lab-Method

Shake-flask method (thermodynamic solubility)

Excess of solid drug exposed to liquid

Final assay after established equilibrium between drug dissolving and drug precipitating at 37 °C

Takes usually 60 – 72 hours with sampling at earlier time points

Sufficient number (n>3 with extrapolation of regression line to y-axis)

Standard USP buffer solutions considered to be appropriate

pH of supernatant needs to be verified

Dose Number

S

Water

CVD

Do

function of drug substance solubility

D / Vwater >> CS ~ High Do D / Vwater << CS ~ Low Do

SolubilityIssues

BCS Class Boundaries

Solubility: Highly soluble drug substance

– FDA: the highest dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1 to 7.5, at 37°C ± 1°C

– EMA: the highest single dose administered is soluble in 250 mL or less of buffer solutions of pH 1 to 6.8, at 37°C ± 1°C

– WHO: the highest dose* is soluble in 250 mL or less of aqueous media pH range of 1.2 to 6.8, at 37°C ± 1°C

* highest dose recommended in WHO’s List of Essential Medicines or the highest dose strength available on the market

Permeability Determination

High permeability

– Complete absorption, generally related to high permeability

Methodology

– Absolute bioavailability: oral BA determination using intravenous administration as a reference

– Mass-balance studies: pharmacokinetic mass balance studies using unlabeled, stable isotopes or a radiolabeled drug substance

– Intestinal permeability methods: • in vivo intestinal perfusion studies (human/animal)

– in vitro permeation studies (excised human/animal tissue)– in vitro permeation studies on cell monolayers (e.g.Caco-2)

Absorption Number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Human Permeability vs. Fraction Dose Absorbed

Amidon G.L. et al. Pharm Res 1995 12: 413-20

BCS Class Boundaries

PermeabilityHighly permeable drug substance:

– FDA: the extent of absorption in humans is greater than 90% of an administered dose– Mass balance

– Absolute bioavailability

– Intestinal permeability– EMA: the extent of absorption in humans is greater than 85% of an

administered dose– Mass balance

– Absolute bioavailability– WHO: the extent of absorption in humans is greater than 85% of an

administered dose – based on mass-balance

– compared with an intravenous reference dose

– Alternative methods are accepted

Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 - 8

1 10 100 1000 10000 100000

0.01

0.1

1.0

10

I

III

II

IV

Dissolution likely to be “rate limiting”

Gastric emptyingdetermines on-set of

absorption

Absorption might be: - incomplete- sensitive to certain excipients

Generally “problem” molecules

Hu

man

Per

me

ab

ility

Biopharmaceutics Classification System

Biopharmaceutics Classification System

Solubilitymg/mL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity

DensityParticle Radius

Residence time in GI Trakt

Time required forcomplete dissolution

Dissolution number

BCS Linked to Dissolution and Absorption

Class I

– High absorption number– High dissolution number – Rate limiting step is

dissolution • If rapid then gastric emptying

rate limiting step

Class II

– High absorption number– Low dissolution number – Rate limiting step is dissolution

• Except a very high dose number

– IVIVC possible

Class III

– Low absorption number– High dissolution number – Rate limiting step is permeability – BA not influenced by dosage form

but alteration of physiology

Class IV

– Low absorption number– Low dissolution number – Rate limiting steps both,

permeability and dissolution– BA highly variable

Extension of the BCS to BDDCS

BDDCS: biopharmaceutical drug disposition classification system (according to Wu and Benet 2005)

– BCS Class I and II drugs are eliminated primarily via metabolism, whereas Class III and IV drugs are eliminated unchanged via bile or urine

– When metabolism is the major route of drug elimination, the drug exhibits high permeation

– Extent of metabolism instead of extent of absorption may be used for categorization

• e.g. class I: > 90 % metabolized may be substituted for > 90 % absorbed

– BDDCS allows for the prediction of transporter-enzyme interactions

Dissolution Testing Requirements for in vitro BE

FDA EMA WHO

Apparatus USP App. 1USP App. 2

BasketPaddle

BasketPaddle

Dissolution media

0.1 N HCl or SGFBuffer pH 4.5Buffer pH 6.8 or SIF

Buffer pH 1.0 or SGFBuffer pH 4.5Buffer pH 6.8 of SIF

Buffer pH 1.2Buffer pH 4.5Buffer pH 6.8

Use of enzymes is allowed in case of gelatin capsules or gelatin coated tablets

Absolutely no addition of surfactant or enzymes is allowed

Int. Ph. Buffers are preferred

Volume 900 ml 900 ml or less 900 ml or less

Temperature 37°C ± 0.5°C 37°C ± 1°C 37°C

Agitation Basket: 100 rpmPaddle: 50 rpmalternatives to be justified

Basket: 100 rpmPaddle: 50 rpm

Basket: 100 rpmPaddle: 75 rpm

Sampling time 10, 15, 20, 30 min 10, 15, 20, 30, 45 min 10, 15, 20, 30, 45, 60 min

Sample # 12 12 12

Requirements f2 ≥ 50 50 ≤ f2 ≤ 100 50 ≤ f2 ≤ 100

Dissolution Characteristics of IR Drug Products

FDA EMA WHO

Very rapidly dissolving

No definition ≥85%of the labeled amount dissolves in 15 min

≥85%of the labeled amount dissolves in 15 min or less

Rapidly dissolving

≥85%of the labeled amount dissolves in 30 min

No definition ≥85%of the labeled amount dissolves in 30 min

Similarly dissolving (EMA)

No definition ≥85%of the labeled amount dissolves between 15 and 30 min

No definition

Test conditions Paddle at 50 rpm orBasket at 100 rpm in900 ml or less of

0.1N HCl or SGFBuffer pH 4.5Buffer pH 6.8 or SIF

Paddle at 50 rpm orBasket at 100 rpm in900 ml or less of

0.1N HCl or SGFBuffer pH 4.5Buffer pH 6.8 or SIF

Paddle at 75 rpm orBasket at 100 rpm in900 ml or less of

Buffer pH 1.2Buffer pH 4.5Buffer pH 6.8

FDA-Requirements for BCS-based Biowaiver

Immediate release drug products onlyBCS-Class I drug substanceRapidly dissolving IR drug productTest and reference drug product are pharmaceutically equivalentTest and reference drug product exhibit similar dissolution profiles

Exclusions

IR drug products considered not to have a narrow therapeutic indexProducts designed to be absorbed in the oral cavity

Biowaiver with Respect to BSC Classification - FDA

IV III

II I

- Solubility +

- P

erm

eabi

lity

+

EMA-Requirements for BCS-based Biowaiver

Restricted for immediate release drug products considered not to have a narrow therapeutic indexCase I

– Same drug substance BCS-Class I or different salt both BCS-Class I

– either very rapid or rapid in vitro dissolution

– Same excipients in similar amounts

– Similarity of dissolution profiles

Case II– Same drug substance BCS-Class III

– very rapid in vitro dissolution

– Same excipients in very similar amounts

– Similarity of dissolution profiles

WHO-Requirements for BCS-based Biowaiver

WHO Model List of Essential Medicines immediate release solid oral dosage formsCase 1

– BCS-Class I drugs

– very rapidly dissolving drug products (both test and reference)

– rapidly dissolving drug products for which similarity of dissolution profiles was demonstrated

Case 2– BCS-Class III drugs

– very rapid in vitro dissolution

– Same composition regarding excipients in both test and reference

WHO-Requirements for BCS-based Biowaiver

WHO Model List of Essential Medicines immediate release solid oral dosage formsCase 3

– BCS-Class II compounds with weak acid properties (high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability)

– rapidly dissolving in pH 6.8 (both test and reference)

– similar of dissolution profiles for both test and reference product in all three buffer media (pH 1.2, 4.5, and 6.8)

– Careful examination of type and amount of surfactant in the formulation

Biowaiver with Respect to BSC Classification - WHO

IV III

II I

- Solubility +

- P

erm

eabi

lity

+

Selection of the Reference Product

The reference product/ comparator – is RLD in the US

– is normally the innovator product for which efficacy, safety and quality has been established (EMA)

– the selection is made at the national level and should be justified (EMA and WHO)

– In case the innovator cannot be identified – WHO comparator product

– ICH innovator product

– Well selected comparator

The assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product

More than one batch of the reference product should be investigated

Dose strength:US-RLD: 875 mgEurope: common dose 500 mgWHO-LEM: 500 mg (as trihydrate)

Solubility: Permeability:1 g / 370 ml 89%875 mg = 324 mL500 mg = 185 mL

BSC Classification:US: Class IVEurope, WHO: Class I

Example: Amoxicillin

Dissolution Cases

High solubility in both pH 1.2 and 6.8– Conduct dissolution according to USP-NF <711> in each pH 1.2 and 6.8

– App. 1@100 rpm or App. 2@50 rpm in 900 mL

– Q=85% in 30 minutes

High solubility in pH 1.2 only– Conduct dissolution according to USP-NF <711> in pH 1.2

– App. 1@100 rpm or App. 2@50 rpm in 900 mL

– Q=85% in 15 minutes

High solubility in pH 6.8 only– Conduct dissolution according to USP-NF <711> in pH 6.8

– App. 1@100 rpm or App. 2@50 rpm in 900 mL

– Q=85% in 15 minutes

Low solubility in both pH values– Product specific development needed

– Suggestions on surfactant usage could be included

Products that meet the acceptance criteria may be considered:To perform optimally orTo be optimally available for in vivo absorption

Products that do not meet the acceptance criteria are not necessarily “bad” products, require additional studies to demonstrate proper performance

Evaluating the results

30

The BCS is the scientific foundation for BiowaiversBiowaivers can be used to approve drug products

– SUPAC

– Generic drug productsHarmonization among different jurisdiction regarding solubility

classification is neededHarmonization in selection of a Reference product

Summary