Development Of Dissolution - PQRI

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Development of DissolutionMethods for BCS Class 2/4 Drugs– A USP PerspectiveDr. Erika StipplerDirectorDosage Form Performance

Dissolution Testing Dissolution assesses the performance of drug productsTo be effective, the test should be:– Predictive- relationship to in vivo response– Comparative- prediction only possible with comparative tests– Discriminatory- comparison only possible with discriminatory tests– Reproducible- discrimination only possible with reproducible tests– Precise- significant differences are based on the variability of the results3

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GC 1092 The Dissolution Procedure:Development and Validation Major revision of the chapter published in PF 40(1) Comments incorporated –̶ http://www.usp.org/sites/default/files/usp pdf/EN/USPNF/usp 3833 1s commentary.pdfOfficial text USP38–NF33 Supplement 1̶Aug. 1, 20155

USP GC 1092 The Dissolution Procedure:Development and Validation Providesgeneral information regarding development andvalidation of dissolution procedures–Preliminary assessment (for early stages of productdevelopment/ dissolution method development)– Performing filter compatibility– Determining solubility and stability of drug substance invarious media– Choosing a dissolution medium and volume– Choosing an apparatus

USP GC 1092 The Dissolution Procedure:Development and Validation–Method development– De-aeration– Sinkers– Agitation– Study design–Analytical finish– Sample processing– Filter– Centrifugation– Analytical procedure– Spectrophotometric analysis– HPLC

USP GC 1092 The Dissolution Procedure:Development and Validation–Automation– Medium preparation– Sample introduction and timing– Sampling and filtration– Cleaning– Operating software and computation of results– Common deviations from the compendial procedure thatmay require validation

USP GC 1092 The Dissolution Procedure:Development and Validation–Validation– Specificity/ placebo interference– Linearity and range– Accuracy and recovery– Precision– Robustness– Stability of standard and sample solutions– Consideration for automation–Acceptance criteria

Solubility of the Drug Substance Thermodynamic solubility – saturationconcentration of the drug–In different aqueous media at 37 C – Shake-flask method (equilibrium solubility)Alternative approachesKinetic solubility - comparison of differentforms/salts of the same compound––Intrinsic dissolutionApparent dissolution10

BCS Classification FDA(2000) HighSolubility: Highest strength should be soluble in 250 mLor less of aqueous media over the pH range of 1- 7.5(at 37 C 1 C) HighPermeability: 90% or greater absolute bio, or urinaryrecovery, or; permeability greater than the referencecompound(s) WHO(2015) Highsolubility: The highest single therapeutic dose is solublein 250 mL or less of aqueous media over the pH range of 1.2 –6.8 (at 37 C 1 C) Highpermeability: Extent of absorption in humans is 85% ormore based on a mass balance determination or in comparisonwith an intravenous comparator dose11

BCS Classification EMA(2010) HighSolubility: highest single dose administered asimmediate is completely dissolved in 250 mL of buffers withinthe range of pH 1 – 6.8 (at 37 C 1 C)Permeability: extent of absorption is 85 % ( datafrom absolute bioavailability studies or mass balance) High12

FDA Draft Guidance May 2015 Drugsubstance solubility class highlysoluble - the highest strength is soluble in 250 mL or less ofaqueous media over the pH range of 1-6.8 Drugsubstance permeability class highlypermeable - the extent of absorption in humans is determined tobe 85% or more of an administered dose based on a mass balancedetermination or in comparison to an intravenous reference dose Instabilityin the gastrointestinal tract 1hour in gastric fluid and 3 hours in intestinal fluid incubated at 37 C.Drug concentrations should be determined using a validated stabilityindicating assay method. Significant degradation ( 5 %) of a drug inthis study could suggest potential instability13

Biopharmaceutics Classification System(BCS) (1)High solubility classD/S 250 mLpH range 1 to 6.8Low solubility classD/S 250 mLpH range 1 to 6.8 Class I – high permeability Class II – high permeability Class III – low permeability Class IV – low permeability14Source: Pharm Res, 1995

Thermodynamic Solubility – Drug Substance pH dependent solubility–– Influence of salt composition– Different composition of buffer solution at the same pH valueUse of solubilizing agents–– Buffer solutions with different pH values (e.g., pH 1 to pH 8)Different buffer solutions may have different solubilizingpropertiesTo improve wettabilityTo improve solubilityEffect of various surfactants (if applicable)––Different surfactant types (e.g., non-ionic, anionic, cationic)Different concentrations of the same surfactant15

pH Dependent Solubility – Folic AcidFolic acid solubility-pH profile (2)Source: International Journal ofPharmaceutics, 2009Solubility of folic acid in water atdifferent pH values and at differenttemperatures (3) (dash-dotted line modelpredicted data at 298.15K line, dash line modelpredicted data at 303.15K, real line model predicteddata at 313.15K, symbols experimental data at298.15K, 303.15K and 313.15K. Dotted line – datataken from literature)16Source: J. Chem. Eng. Data, 2010

Folic Acid Tablets Monograph USP40-NF35 PERFORMANCE TESTS DISSOLUTION 〈711〉 Medium: Water; 500 mL Apparatus 2: 50 rpm Time: 45 min Standard solution: Solution having a known concentration of USP FolicAcid RS, corrected for water content, in Medium Sample solution: Filtered portion of the solution under test, suitablydiluted with the Medium if necessary17

Low Solubility Drug: Weak Acid – Ibuprofen (4) Highest dose 800 mghighest Dose [mg ]D/S 250mLsaturation concentration [mg / mL ]No1MediumSimulated Gastric Fluid, SGFsp,pH value ofConcentration ofDose/Solubilitysaturatedsaturatedof the highestsolutionsolution [mg/mL]dose [mL]1.20.037021609.9pH 1.22Purified water, pH 5.85.60.08948944.53Simulated Intestinal Fluid,6.72.472323.627.04.524176.83SIFsp, pH 6.84Phosphate buffer solutionpH 7.218Source: Ph.D Thesis, Shaker Verlag, 2006

Ibuprofen Tablets Monograph USP40-NF35 PERFORMANCE TESTS Dissolution 〈711〉 Medium: pH 7.2 phosphate buffer (see Reagents, Indicators, andSolutions—Buffers); 900 mL Apparatus 2: 50 rpm Time: 60 min Standard solution: A known concentration of USP Ibuprofen RS inMedium Sample solution: Filter a portion of the solution under test, and suitablydilute with Medium if necessary. Instrumental conditions Mode: UV Analytical wavelength: Maximum absorbance at about 221 nm19

Low Solubility Drug – Carbamazepine (4)pH independent solubilityNo1MediumSimulated Gastric Fluid,pH value ofConcentration ofDose/Solubilitysaturatedsaturated solutionof the highestsolution[µg/mL]dose [mL]1.2191.92084.4SGFsp, pH 1.22Purified water, pH 5.55.5224.21784.13FaSSIF-blank, pH 6.56.5144.72764.34Simulated Intestinal Fluid,6.8191.42089.96.8163.92440.5SIFsp, pH 6.85Modified Simulated IntestinalFluid, Na-SIFsp, pH 6.8D/S highest Dose [mg ] 250mLsaturation concentration [mg / mL ]20Source: Ph.D Thesis, Shaker Verlag, 2006

Low Solubility Drug – Carbamazepine (4)Selection of the suitable surfactantNoSurface active Solubilityof surfactant atof saturatedof the highesttenfold highersolutiondose [mL]than CMC [%][µg/mL]0144.72764.3FaSSIF-blank Pluronic F680.1261.11532.03FaSSIF-blank Triton X1000.2524.2763.14FaSSIF-blank Brij 350.1274.21458.85FaSSIF-blank Tween 800.2304.61313.26FaSSIF-blank Texapon N400.2468.0854.77FaSSIF-blank SLS0.31092.7366.1D/S highest Dose [mg ] 250mLsaturation concentration [mg / mL ]21Source: Ph.D Thesis, Shaker Verlag, 2006

Low Solubility Drug: Carbamazepine (5)Evaluation of the appropriate surfactant concentrationNo Medium1SGFsp, pH 1.22ConcentrationConcentration ofDose/Solubility ofof SLS [%]saturated solutionthe highest dose[µg/mL][mL]0191.92084.4SGFsp 0.3 % SLS0.3803.0498.13SGFsp 0.5 % SLS0.51255.3318.64SGFsp 1.0 % SLS1.02346.4170.55SGFsp 2.0 % SLS2.04722.084.722Source: Ph.D Thesis, Shaker Verlag, 2006

Carbamazepin Tablets Monograph USP40-NF35 PERFORMANCE TESTS DISSOLUTION 〈711〉 Test 1: If the product complies with this test, the labeling indicates that it meetsFor products labeled as 100-mg chewable TabletsUSP Dissolution Test 1. Medium: Water containing 1% sodium lauryl sulfate; 900 mL Apparatus 2: 75 rpm Time: 60 min Standard solution: USP Carbamazepine RS in Medium. [NOTE—A volume of methanolNMT 1% of the final total volume of the Standard solution may be used to dissolve thecarbamazepine.] Sample solution: Filtered portion of the solution under test, diluted with Medium if necessary Instrumental conditions Mode: UV Analytical wavelength: Maximum absorbance at about 288 nm23

Carbamazepin Tablets Monograph USP40-NF35 PERFORMANCE TESTS DISSOLUTION 〈711〉 For products labeled as 200-mg Tablets Test 2: If the product complies with this test, the labeling indicates that itmeets USP Dissolution Test 2. Medium, Apparatus 2, Standard solution, Samplesolution, and Instrumental conditions: Proceed as directed in Test 1. Test 3: If the product complies with this test, the labeling indicates that itmeets USP Dissolution Test 3. Medium, Apparatus 2, Standard solution, Samplesolution, and Instrumental conditions: Proceed as indicated in Test 1.24

USP Dissolution Method Databaseabbreviations:SGF simulated gastric fluidUSP Dissolution Methods DatabaseUpdated Feb 15, 2017,with the release of the First Suppl. of USP 40 – NF 35SIF simulated intestinal fluidSLS sodium lauryl sulfate (sodium dodecylTERMS OF USE: Copyright the United States Pharmacopeial Convention (USP). All rights reserved. The database content issulfate)not intended to and does not constitute legal advice and is not warranted or guaranteed by USP. Your use of database contentis at your own risk. USP accepts no responsibility or legal liability for the use and/or accuracy of the database or for decisions w/ withmade based on this data.w/o withoutTIP: Search and sort by clicking on arrows in cells on top row. Drop down box with options will appear.MONOGRAPHTOTAL TEST QUANTITATIVE .6 - MEDIUMSURFACTANTpHAcitretin Capsules13% SLS in waterSLS9.6 - 10.0Acitretin Capsules23% SLS in waterSLSAcitretin Capsules2 Tier 2 Medium A1750 USP unitspancreatin inwaterAcitretin Capsules2 Tier 2 Medium B 6% SLS in n w/caps shellsolutionTier 1Medium: 3% sodium lauryl sulfate in deaerated water, pH 9.6–10.0 (adjusted with 1 N sodium hydroxide); 900 mLApparatus 1: 100 rpmTime: 30 minTier 2Medium A: Prepare a solution containing pancreatin with NMT 1750 USP units of protease activity/L in deaerated water, pH8.0 (adjusted with 1% sodium hydroxide); 450 mL, use immediately.Medium B: 6% sodium lauryl sulfate in deaerated water, pH 10.5 (adjusted with 1% sodium hydroxide); 450 mLApparatus 1: 100 rpmTime: 10 min Medium A; 20 min Medium A with the addition of Medium B25

Dissolution Medium used in Monographs Additionof surface active agents–Synthetic surfactants––––––––––Sodium lauryl sulfate concentration varying between 0.02% and 6%Polysorbate 80 concentration varying between 5ppm and 3%Polysorbate 20: concentration varying between 0.35% and1.0%Polysorbate 40: 2.0%Polyoxyethylene(23)laurylether 0.6%Polyoxyethylene(10)laurylether concentration varying 25mM - 60mMHexadecyltrimethylammonium bromide 0.0014MCetyltrimethylammonium bromide 0.01%Hydroxypropylcellulose in water 1 in 2000Lauryl dimethylamine oxide concentration varying 0.1% - 4.5%–Enzymes– pepsin– pancreatin–Alcohol– isopropanol 30% (e.g. Oxandrolone tablets)

Stability of Drug Substance in DissolutionMedium at 20 C 2 C (*) Chlorpheniramine: concentration 0.04 mg/mLSGF blankSIF tial267484%RSD1.24027

Stability of Drug Substance in DissolutionMedium at 20 C 2 C (*) Diphenhydramine HCl: concentration 0.05 mg/mLSGF blankStability4hr8hr12hr24hr48hrArea %Diff.341698 -3.2NANA340231 -3.6333093 -5.6324312 -8.1SIF Diff.0.81.01.30.50.73771630.19328

Selection of Apparatus Based on the knowledge of the design and the technicalaspects of the dosage form performance For solid oral dosage forms––– Apparatus 1 and Apparatus 2 are used most frequentlyApparatus 3: chewable tablets, delayed release dosage formsApparatus 4: various dosage formsSome changes can be made to the apparatus when theneed is clearly documented by supporting data–Basket mesh size29

Selection of the Volume of Dissolution Medium Basket/ Paddle Apparatus–– Reciprocating Cylinder Apparatus–– Up to 250 mL/vesselUse of up to 6 rows for testing for a sampleFlow-through Cell Apparatus––– Generally: 500 mL – 1000 mLSpecial cases: 2 or 4 literGenerally: 4 mL/min – 16 mL/minFor implants: 1 mL/min – 2 mL/min, or lessSpecial cases: up to 50 mL/minReciprocating holder30

Selection of the Volume of Dissolution MediumDissolution of Carbamazepine drug substance (4)100% of carbamazepine amount dissolved% of carbamazepine amount dissolved100806040900 mL deionized water 1.0% SLS900 mL SGFsp, pH 1.2 0.5% SLS900 mL Na-SIFsp, pH 6.8 0.5% SLS200806040001020304050time / min60708090carbamazepine pH900900 mL deionized water 1.0% SLS500 mL SGFsp, pH 1.2 0.5% SLS500 mL Na-SIFsp, pH 6.8 0.5% SLS20010203040time / min5060carbamazepine pH50031Source: Ph.D Thesis, Shaker Verlag, 2006

Discriminating Dissolution Method for IR BCSClass II Soft Gelatin Capsule Formulation (6)MediumpH 2 - 0.1 N HClpH 6.8 - phosphate bufferpH 12.5 - bufferSolubility484.27 μg/mL4.32 μg/mL3.16 μg/mL32

Loratadine Tablets Monograph USP40-NF35PERFORMANCE TESTS DISSOLUTION 〈711〉Medium: 0.1 N hydrochloric acid; 900 mLApparatus 2: 50 rpmTime: 60 minStandard solution: USP Loratadine RS at a known concentrationin MediumSample solution: A filtered portion of the solution under test, suitablydiluted with Medium, if necessaryInstrumental conditions Mode: UV-VisAnalytical wavelength: Maximum absorbance at about 280 nm33

Dissolution Profiles of Gliclazide MR Tablets (5)Gliclazide – weak acid (pKa 5.8)Fig. 1. Dissolution profiles of Azukon MR 30 mg in apparatus 1,at different pH values and at a 50 and b 100 rpmFig. 2. Dissolution profiles of Azukon MR 30 mg in apparatus 2,At different pH values and at a 50 and b 100 rpm34Source: AAPS PharmSciTech, 2016

Dissolution Profiles of Gliclazide MR TabletsSelection of apparatus (5)Fig. 3. Dissolution profiles of Azukon MR 30 mg inapparatus 3, at pH 6.8 and pH gradient, mimickingthe physiological conditionsVessel row1pH4.5Residence time (min)60234565.56.07.06.46.83012090300840Fig. 5. Comparison of the dissolution profiles of Azukon MR 30 mgin apparatuses 1, 2, and 3, at 100 rpm, 50 rpm, and 10 dpm,respectively35Source: AAPS PharmSciTech, 2016

Conclusions Evaluation of the solubility and stability of the drugin various aqueous media is critical in the dissolutionmethod development Choice of dissolution testing conditions is based on–Solubility of the drug substance–Maintain sink-conditionsStability of the drug substanceProperties of the dosage formRelease mechanismCompendial dissolution apparatus–Preferred useNon-compendial apparatus ––– 36

References 1. Amidon G.L., Lennernäs H., Shah V.P., Crison J.R., A theoretical basis for abiopharmaceutic drug classification: the correlation of in vitro drug productdissolution and in vivo bioavailability, Pharm Res 12, 1995, 413 2. Islam R. Younisa, Mary K. Stamatakisb, Patrick S. Callerya, Paula Jo. MeyerStout, Influence of pH on the dissolution of folic acid supplements, InternationalJournal of Pharmaceutics 367, 2009, 97–102 3. Zhen Wu, Xiuxi Li, Chunyan Hou, and Yu Qian, Solubility of Folic Acid inWater at pH Values between 0 and 7 at Temperatures (298.15, 303.15, and313.15K), J. Chem. Eng. Data 55, 2010, 3958–3961 4. Stippler ES, Biorelevant dissolution test methods, Ph.D Thesis, ShakerVerlag, 2006 5. Skripnik KKS, Riekes MK, Pezzini BR, Cardoso SG, Stulzer HK,Investigation of the dissolution profile of Gliclazide modified-release tabletsusing different apparatus and dissolution conditions, AAPS PharmSciTech,201637

References 6. Festo D, Marati M, Pathak V, Schwartzenhauer J, Development of adiscriminating dissolution method for immediate-release soft gelatin capsulescontaining a BCS Class II compound, Diss. Techn. 23 Issue 4, 2016, 6-1338

Relevant GuidelinesFDAGuidance for Industry Waiver of In Vivo Bioavailability andBioequivalence Studies for Immediate-Release Oral Dosage FormsBased on a Biopharmaceutics Classification System, Aug. 2000- DRAFT Revised version – May 2015WHOWHO Technical Report Series No. 937: WHO EXPERT COMMITTEEON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS,Fortieth Report, Annex 7, 2006- WHO Technical Report Series No. 992: ANNEX 7, 2015EMAGUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCEDoc. Ref.: CPMP/QWP/EWP/1401/98 Rev. 1, Jan. 201039

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development/ dissolution method development) –Performing filter compatibility –Determining solubility and stability of drug substance in various media –Choosing a dissolution medium and volume –Choosing an apparatus . USP GC 1092 The Dissolution Procedure: Development and Validation

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