klein

TheThe UseUse of Biorelevant of Biorelevant DissolutionDissolution Media Media

to to ForecastForecast thethe In VivoIn Vivo Performance of a DrugPerformance of a Drug

AAPS Workshop on the Role of Dissolution AAPS Workshop on the Role of Dissolution

in in QbDQbD and Drug Product Life Cycle and Drug Product Life Cycle

April 28April 28--30, 2008, Arlington, VA30, 2008, Arlington, VA

Dr. Sandra Klein

Institute of Pharmaceutical Technology

Johann Wolfgang Goethe University Frankfurt

Dr. Sandra Klein, 04/2008

• to evaluate product quality immediately

after manufacture and during the shelf-life

• to evaluate product quality after changes

in composition or manufacturing method

(SUPAC)

• to compare formulations during

development

„„ClassicalClassical““ applicationsapplications of of dissolutiondissolution testingtesting


• examining bioequivalence of different drug products

• predict the in vivo release in terms of IVIVC

Is it possible to predict the in vivo performance of a drug and therelease of a dosage form using simple dissolution tests ?

biorelevant dissolution tests

simulation of conditions in the human gastrointestinal tractthat may affect the dissolution process

„„ModernModern““ applicationsapplications of of dissolutiondissolution testingtesting


Human GI Human GI tracttract

StomachpH = 1-3 (fasted)

pH = 4-7 (fed)


DuodenumpH = 4-6bile and pancreatic secretion



JejunumpH = 6-7, slightly lower in the fed state



IleumpH = 7-7.5



ColonpH = 5-7



Selection of test conditionsSelection of test conditions

• classify the drug substance according to the BCS

characterize the drug solubilityover the pH range 1.2 to 6.8(BCS classification)

run dissolution tests with the pure drugto determine whetherthere are any wetting problems

• choose appropriate media (pH, composition) and volumes


Classification of drug substances according to the BCS

Guidance for Industry: Immediate release solid oral dosage formsGuidance for Industry: Immediate release solid oral dosage forms, FDA, 1995, FDA, 1995

BBiopharmaceuticsiopharmaceutics CClassificationlassificationSSchemecheme

CLASS 1 CLASS 2

highly soluble poorly soluble

highly permeable highly permeable

CLASS 3 CLASS 4

highly soluble poorly soluble

poorly permeable poorly permeable


DissolutionDissolution teststests forfor highlyhighlysolublesoluble drugsdrugs ((ClassClass I and I and ClassClass III) III) Class I:Acetaminophen: 14.5 mg/ml → D/S ca. 22.4 ml

neutral85-90% bioavailability

Metoprolol: > 1 g/ml (-tartrate) → D/S < 1 mlpKa 9.7 (weak base)~ 100% bioavailability

Class III:Aciclovir: 1.3 mg/ml → D/S ca. 150 ml

neutralca. 20% bioavailability


DissolutionDissolution media media forfor highlyhighlysolublesoluble drugsdrugs ((ClassClass I and I and ClassClass III) III)

• a simple medium is sufficient!

• USP media or aqueous buffers, e.g.:

→ SGFsp pH 1.2

→ Acetate buffer pH 4.5

→ SIFsp pH 6.8

• avoid water: no buffer capacity → variable pH


Test setup• Paddle apparatus• 500 ml medium• SIFsp or IP Phosphate buffer pH 6.8• 75 rpm• 37°C• sampling after 30 min

Specification• > 85 % release within 30 min

ProposedProposed simplifiedsimplified test test methodmethod forfor IR IR dosagedosage formsforms withwith highlyhighly solublesoluble drugsdrugs

http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdfhttp://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf


DevelopingDeveloping dissolutiondissolution teststests forfor poorlypoorlysolublesoluble drugsdrugs ((ClassClass II and II and ClassClass IV) IV)

Weak acids D/S LITERS !Troglitazone 2 µg/ml pKa 6.1 100Glyburide < 0.1 µg/ml pKa 5.3 >> 36Phenytoin 27 µg/ml pKa 8.3 3.7

Neutral substancesDanazol 0.5 µg/ml 200Atovaquone 0.1 µg/ml (pKa 9) 1,785Felodipine 1 µg/ml 10Griseofulvin 15 µg/ml 16.6

Weak basesKetoconazole 4.7 µg/ml pKa 2.9; 6.5 44.4Itraconazole < 0.001 µg/ml pKa 3.7 >> 100,000Tamoxifen 3.3 µg/ml pKa 8.8 12


• solubility of lipophilic compounds (typically logP > 2) is better in

presence of bile salt / lecithin micelles

• solubility of weak bases is often best in the stomach, that of

weak acids in the small intestine

• solubilites in the GI tract may far exceed the aqueous solubility

→ dissolution is often better in vivo !!!

SolubilitySolubility in in thethe GI GI tracttract comparedcomparedto to aqueousaqueous solubilitysolubility


DissolutionDissolution media media forfor ClassClass II and II and ClassClass IV IV substancessubstances

LocationLocation prepre--//postprandialpostprandial MediumMedium

Stomach preprandial SGFsp (USP) plus surfactant z.B. Triton X 100, SDSFaSSGF

Stomach postprandial Ensure® Plus, Milk

Small intestine preprandial FaSSIF

Small intestine postprandial FeSSIF


In In vitrovitro simulationsimulation of of thethe preprandialpreprandialStomachStomach, , „„SGFplusSGFplus““

Sodium chloride 2 gHydrochloric acid conc. 3 gTriton X 100 1 gDeionized water qs ad 1 liter

pH 1.8Osmolality [mOsmol/kg] 120Surface tension [mN/m] 31

SGF plus pH 1.8


FFastedasted SState tate SSimulatedimulated GGastricastricFFluidluid„„BiorelevantBiorelevant““ Simulation of Simulation of conditionsconditions in in thethe fastedfasted stomachstomach


3,3 % proteins

4,7 % carbohydrates

4 % fat

•• wholewhole milkmilk or a standardized nutritionalfluid e.g. EnsureEnsure®® PlusPlus to simulate initial composition after a standardized breakfast

Macheras et al. Macheras et al. Int. J. Int. J. PharmPharm. 33: 125. 33: 125--136 (1986)136 (1986)

Klein et al. Klein et al. J. J. PharmPharm. . PharmacolPharmacol. 56: 605. 56: 605--610 (2004)610 (2004)

In In vitrovitro simulationsimulation of of thethepostprandialpostprandial stomachstomach


PostprandialPostprandial StomachStomach

„Biorelevant“ Simulation of the physicochemical properties in thestomach immedaiately after administration of a standard breakfast

ENSURE PLUSENSURE PLUS®®

Standard Breakfast FDA Division of Biopharmaceutics

2 slices of toasted white bread with butter2 eggs fried in butter2 slices of bacon2 ounces of hash-browned ( fried shradded ) potatoes = 56,7 g8 ounces of whole milk

Carbohydrate: 58g, 232 kcal, 972 kJ, 24 %Protein: 33g, 132 kcal, 552 kJ, 14 %Fat: 67 g, 603 kcal, 2533 kJ, 62 %


In In vitrovitro simulationsimulation of of thethe fastedfasted SISIFaFastedsted SStatetate SSimulatedimulated IIntestinalntestinal FFluidluid

Sodium taurocholate 3 mMLecithin 0.75 mMNaH2PO4 3.438 gNaCl 6.186 gNaOH qs ad pH 6.5Deionized water qs ad 1 liter

pHOsmolality [mOsmol/kg]Buffer capacity [mEq/pH/L]Surface tension [mN/m]

FaSSIF

54

6.5~ 270 *

~ 12


In In vitrovitro simulationsimulation of of thethe fedfed SISIFeFedd SStatetate SSimulatedimulated IIntestinalntestinal FFluidluid

Sodium taurocholate 15 mMLecithin 3 mMAcetic acid 8.65 gNaCl 11.874 gNaOH pellets 4.04 gDeionized water qs ad 1 liter

pHOsmolality [mOsmol/kg]Buffer capacity [mEq/pH/L]Surface tension [mN/m] 48

FeSSIF

5.0~ 670*

72


In In vitrovitro simulationsimulation of of thethe coloncolonSSimulatedimulated CColonicolonic FFluidluid

1M Acetic acid 170 ml1M NaOH 157 mlDeionized water qs ad 1 liter

pHOsmolality [mOsmol/kg]Buffer capacity [mEq/pH/L]Surface tension [mN/m]

SCoF pH 5.8

70

5.829529


Case example: Danazol (neutral compound, BCS Class II)

Aqueous solubility: 1µg/ml D:S = 200 litres H20Dose: 200 mg 20 litres FaSSIFpKa: neutral 6 litres FeSSIFlogP: 4.53

DoesDoes a a mealmeal increaseincrease thethe biobio--availabilityavailability of a drug of a drug substancesubstance ??


DanazolDanazol DissolutionDissolution profilesprofiles in in variousvarious media at 100 media at 100 rpmrpm

postprandial

preprandial

compendial


CharmanCharman et al., et al., J. J. ClinClin. Pharm. Pharm. 33: 1207. 33: 1207--1213 (1993) 1213 (1993)

Food Food effectseffects on on bioavailabilitybioavailability of of DanazolDanazol

preprandial

postprandial


OfficialOfficial Test Test MethodMethod

Danazol Capsules (USP)

Medium: 0.75 % sodium lauryl sulfate solution, 900 mL

Apparatus 2: 75 rpm

Time: 30 minutes

Procedure: measure UV absorbance at 286 nm in comparisonwith a standard solution having a known concentrationof USP danazol

Tolerance: n.l.t. 75% (Q) of the labeled amount of danazol isdissolved in 30 minutes


0,001

0,01

0,1

1

10

100

1 2 3 4 5 6 7 8 9 10

pH

Solu

bilit

y [µ

g/m

l]

Free Acid Free Base

pH/pH/SolubilitySolubility profileprofile of of weakweakacidsacids//basesbases


• dissolution in the stomach is likely to be poor due to the low pH and likely to begin in the more neutral small intestine

• the pH of the medium should be pH >> pKa where possible

If applicable, conditions of the upper or mid small intestineshould be used (pH 5-7)

a typical pH would be pH 6.8 (e.g. SIF pH 6.8)

• if the compound is lipophilic, bile components may boost thesolubility in vivo

DissolutionDissolution propertiesproperties of of poorlypoorlysolublesoluble weakweak acidsacids


Case example: Troglitazone (BCS Class II)

Aqueous solubility: 2 µg/mlDose: 200-400 mg (antidiabetic)pKa: 6.1; 12

IsIs itit possiblepossible to to predictpredict thethe plasmaplasmaprofileprofile of of weakweak acidsacids??


Romozin® tablets

NicolaidesNicolaides et al. et al. PharmPharm. Res. Res. 16: 1876. 16: 1876--1882 (1999)1882 (1999)

DissolutionDissolution profilesprofiles of of TroglitazoneTroglitazonein in thethe fastedfasted and and thethe fedfed statestate


BioavailabilityBioavailability of of TroglitazoneTroglitazone

NicolaidesNicolaides et al. et al. PharmPharm. Res. Res. 16: 1876. 16: 1876--1882 (1999)1882 (1999)


Case example: Phenytoin (BCS Class II)

Aqueous solubility: 27 µg/mlDose: 100 mg (antiepileptic)pKa: 8.3

IsIs itit possiblepossible to to predictpredict thethe plasmaplasmaprofileprofile of of weakweak acidsacids??


SolubilitySolubility of of PhenytoinPhenytoin in different in different test media test media

0

10

20

30

40

50

60

Wate

rSGFsp

USP 28

SGFsp m

od.

Acetat

e buff

erBlan

k FaS

SIFBlan

k FeS

SIF

FaSSIF

FeSSIF

Acetat

e buff

erSIFsp

USP28

drug

in s

olut

ion

(ug/

ml)


Phenytoin AWD 100 mg tablets

DissolutionDissolution profilesprofiles of of PhenytoinPhenytoinin in thethe fastedfasted and and thethe fedfed statestate

0

5

10

15

20

25

0 30 60 90 120

Time (min)

% R

elea

se

FeSSIF pH 5.0

FaSSIF pH 6.5

Blank FeSSIF pH 5.0

Blank FaSSIF pH 6.5


BioavailabilityBioavailability of of PhenytoinPhenytoin

A A MelanderMelander et al. et al. EuropEurop. J. Clinical . J. Clinical PharmacolPharmacol. 15 269. 15 269--274 (1979)274 (1979)


• to characterize the compound, perform dissolution in all biorelevant media

the pH will be most favourable in the fasting stomach, but (iflipophilic) the bile salts may also contribute to solubilization

• in the fasted state the primary site of dissolution is usually thestomach, but caution: many patients are also receiving protonpump inhibitors or H2 receptor antagonists

• in the postprandial state, the greater concentration of bile in theGI tract can compensate for the initial higher gastric pH

DissolutionDissolution propertiesproperties of of poorlypoorlysolublesoluble weakweak basesbases


Case example: Ketoconazole (BCS Class II)

Aqueous Solubility: 4.7 µg/mlpKa: 2.9 / 6.5

IsIs itit possiblepossible to to predictpredict thethe plasmaplasmaprofileprofile of of weakweak basesbases??


KetoconazoleKetoconazole DissolutionDissolution profilesprofilesIn In variousvarious media at 100 media at 100 rpmrpm

0

20

40

60

80

100

0 20 40 60 80 100 120Time [min]

Rel

ease

[%]

300 ml SGFsp

1000 ml FeSSIF

500 ml FaSSIF

900 ml SIFsp


BioavailabilityBioavailability of of KetoconazoleKetoconazole


SummarySummary

• screen the physicochemical properties of the drug

• start with examining the drug under different pH conditions

• characterize the drug solubility over the pH range 1.2 to 6.8

• run dissolution tests with the pure drug to determine whetherthere are any wetting problems

• after characterization of the drug select an adequate biorelevant medium to predict the in vivo performance of your formulation


FIP Guidelines for dissolution testing of solid oral products. In e.g. Die Pharmazeutische Industrie 59:760-766 (1997), or Dissolution Technologies 4:5-14 (1997).

JB Dressman, GL Amidon, C Reppas, VP Shah. Dissolution testing as a prognostic tool for drug absorption: immediate release dosage forms. Pharm. Res. 15: 11-22 (1998)

E. Galia, E Nicolaides, D Hörter, R Löbenberg, C Reppas, JB Dressman. Evaluation of various dissolution media for predicting in vivo performance of Class I and II drugs. Pharm. Res. 15: 698-705 (1998)

E. Galia, J Horton, JB Dressman. Albendazole Generics – A comparative in vitro study. Pharm. Res.16:1872-1876 (1999)

R. Löbenberg, J Krämer, V Shah, GL Amidon, JB Dressman. Dissolution testing as a prognostic tool for drug absorption: Dissolution behaviour of glibenclamide, a case II compound. Pharm. Res. 17: 439-444 (2000)

JB Dressman, H Lennernäs. Oral Drug Absorption, Drugs and the pharmaceutical sciences Volume 106. Marcel Dekker (www.dekker.com) ISBN 0-8247-0272-7. (2000)

JB Dressman, J Butler, J Hempenstall, C Reppas. The BCS: Where do we go from here? PharmacetuticalTechnology 25: 68-76 (2001)

B Rohrs. Dissolution method development for poorly soluble compounds.Dissolution Technologies 8:6-12 (2001)

LiteratureLiterature


E Stippler Biorelevant Dissolution Test Methods to Assess Bioequivalence of Drug Products. Doctoral Thesis. Institut für Pharmazeutische Technologie. Frankfurt, Johann Wolfgang Goethe-Universität.Shaker Verlag: ISBN 3-8322-3218-4 (2004).

S Klein. Biorelevant Dissolution Test Methods for Modified Release Dosage Forms. Doctoral Thesis. Institut für Pharmazeutische Technologie. Frankfurt, Johann Wolfgang Goethe-Universität: Shaker Verlag: ISBN 3-8322-4276-7 (2005).

S Klein. J Butler, J Hempenstall, C Reppas, JB Dressman. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol 56(5): 605-10 (2004).

S Klein, JB Dressman. Simplification of biorelevant media to prescreen solubility and dissolution performance of poorly soluble drugs. Abstract, AAPS Annual meeting, Baltimore (2004)

LiteratureLiterature

klein

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