6 th annual science and standards symposium january 16, 2013 istanbul determination of solubility...
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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