1. 6 th Annual Science and Standards Symposium January 16, 2013 Istanbul Determination of Solubility and Permeability in BCS Erika Stippler, Ph.D. Director Dosage Form Performance Laboratory

2. 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

3. Drug Release – The Rate Limiting Step Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

4. Class Solubility Permeability I High High II Low High III High Low IV Low Low Solubility directly influences the dissolution behavior of oral dosage forms in gastrointestinal tract Biopharmaceutical Drug Classification System (BCS)

5. 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

6. 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.

7. 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

8. Dose Number function of drug substance solubility D / V water >> C S ~ High Do D / V water << C S ~ Low Do Solubility Issues

9. 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

10. 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)

11. Absorption Number Effective permeability Radius of GI Residence time in GI Time required for complete absorption

12. Human Permeability vs. Fraction Dose Absorbed Amidon G.L. et al. Pharm Res 1995 12: 413-20

13. BCS Class Boundaries  Permeability  Highly 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

14. Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 - 8 1101001000 10000 100000 0.01 0.1 1.0 10 I III II IV Dissolution likely to be “rate limiting” Gastric emptying determines on-set of absorption Absorption might be: - incomplete - sensitive to certain excipients Generally “problem” molecules Human Permeability Biopharmaceutics Classification System

15. Solubility mg/mL Diffusivity Density Particle Radius Residence time in GI Trakt Time required for complete dissolution Dissolution number

16. 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

17. Fraction of Dose Absorbed In Relation to Dose Number and Dissolution Number From Löbenberg and Amidon (2000) An Absorption number Dn Dissolution number Do Dose number Fa Fraction absorbed DigoxinGriseofulvin Dose0.5500 mg C s 0.0240.015 mg/ml V sol 20.8 33,333 ml Do0.08133 Dn0.520.32

18. 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

19. Dissolution Testing Requirements for in vitro BE FDAEMAWHO ApparatusUSP App. 1 USP App. 2 Basket Paddle Basket Paddle Dissolution media 0.1 N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF Buffer pH 1.0 or SGF Buffer pH 4.5 Buffer pH 6.8 of SIF Buffer pH 1.2 Buffer pH 4.5 Buffer 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 Volume900 ml900 ml or less Temperature37°C ± 0.5°C37°C ± 1°C37°C AgitationBasket: 100 rpm Paddle: 50 rpm alternatives to be justified Basket: 100 rpm Paddle: 50 rpm Basket: 100 rpm Paddle: 75 rpm Sampling time10, 15, 20, 30 min10, 15, 20, 30, 45 min10, 15, 20, 30, 45, 60 min Sample #12 Requirementsf2 ≥ 5050 ≤ f2 ≤ 100

20. Dissolution Characteristics of IR Drug Products FDAEMAWHO 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 conditionsPaddle at 50 rpm or Basket at 100 rpm in 900 ml or less of 0.1N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF Paddle at 50 rpm or Basket at 100 rpm in 900 ml or less of 0.1N HCl or SGF Buffer pH 4.5 Buffer pH 6.8 or SIF Paddle at 75 rpm or Basket at 100 rpm in 900 ml or less of Buffer pH 1.2 Buffer pH 4.5 Buffer pH 6.8

21. FDA-Requirements for BCS-based Biowaiver  Immediate release drug products only  BCS-Class I drug substance  Rapidly dissolving IR drug product  Test and reference drug product are pharmaceutically equivalent  Test and reference drug product exhibit similar dissolution profiles  Exclusions  IR drug products considered not to have a narrow therapeutic index  Products designed to be absorbed in the oral cavity

22. Biowaiver with Respect to BSC Classification - FDA IVIII III - Solubility+ - Permeability +

23. EMA-Requirements for BCS-based Biowaiver  Restricted for immediate release drug products considered not to have a narrow therapeutic index  Case 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

24. WHO-Requirements for BCS-based Biowaiver  WHO Model List of Essential Medicines immediate release solid oral dosage forms  Case 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

25. WHO-Requirements for BCS-based Biowaiver  WHO Model List of Essential Medicines immediate release solid oral dosage forms  Case 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

26. Biowaiver with Respect to BSC Classification - WHO IVIII III - Solubility+ - Permeability +

27. 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

28.  Dose strength:  US-RLD: 875 mg  Europe: common dose 500 mg  WHO-LEM:500 mg (as trihydrate) Solubility:Permeability:  1 g / 370 ml89%  875 mg = 324 mL  500 mg = 185 mL BSC Classification:  US:Class IV  Europe, WHO: Class I Example: Amoxicillin

29. Dissolution Cases  High solubility in both pH 1.2 and 6.8 –Conduct dissolution according to USP-NF 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 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 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

30.  Products that meet the acceptance criteria may be considered:  To perform optimally or  To 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

31.  The BCS is the scientific foundation for Biowaivers  Biowaivers can be used to approve drug products – SUPAC –Generic drug products  Harmonization among different jurisdiction regarding solubility classification is needed  Harmonization in selection of a Reference product Summary