dissolution testing_usp workshop_2014 final

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Jian-Hwa HanUSP Workshop on Dissolution Testing of CapsulesMarch 24, 2014Crosslinking and Dissolution Testing Method Development & VerificationSUB-TITLE, DATE

A1999587

Preliminary Assessment for Dissolution Method DevelopmentThe Basics - Gelatin Dissolution Dissolution of Acetaminophen - Tablet vs. CapsuleCross-linked Gelatin Impact to DissolutionTier-2 Testing Performance EvaluationEnzymes Information (Current USP )Control of Experiments Tighten the ResultsSetting the Reference Point - Pepsin Evaluation of New Enzymes for pH 4.5Proposed Use of Bromelain and Papain Summary & Next StepPresentation Outline2USP Dissolution Workshop, 2014

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Know Your Product From API to Product DesignUSP Dissolution Workshop, 20143

PowderGranulesPelletsTablets/MiniTabsLiquidHybridIRDRER

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Gelatin Dissolution The Basics

Gelatin Dissolution Typical Media5Data clearly show much faster dissolution rate in 0.1N HClThe dissolution rates in pH 4.5, pH 6.8, and water are similar

USP Dissolution Workshop, 2014

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Gelatin Dissolution Surfactant Impact in Water6Surfactants do slow down the dissolution of gelatinThe impact from POE and CTAB are not significantSDS slowed down more, but the impact should be evaluated by product performance

SDSUSP Dissolution Workshop, 2014

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Gelatin Dissolution Surfactant Impact in pH 6.8 Phosphate Media7No significant impact observed in pH 6.8 Phosphate media with either SDS or POE10LE


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Gelatin Dissolution Surfactant Impact in 0.1N HCl Media8No significant impact observed for POE in 0.1N HCl mediaSignificant impact observed for SDS in 0.1N HCl media!!!

SDSUSP Dissolution Workshop, 2014

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Dissolution ofAcetaminophen:Tablet vs. Capsule

Q: NLT 80% in 30 min.

Reference Compound Acetaminophen10Tylenol 250 mg Tablet was used as the test drugSize 0 HGC Used for the OE sample without filler


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Tablet vs. OE Capsule Dissolution Typical Media11

Tablet: Full release (>85%) within 3 minutes (for all conditions) Once capsule opens, the residual gelatin does not impact dissolution for this product. Full release (>85%) within 10 minutes from OE Capsule (for all conditions) 0.1N HClpH 4.5pH 6.8WaterUSP Dissolution Workshop, 2014

11OE Capsule Samples: (i) 0.1N HCl 95.6 +/- 0.13%; (ii) pH 4.5 93.0 +/- 5.7%; (iii) pH 6.8 93.2 +/- 4.9%; and (iv) Water -98.5 +/- 0.13%.

Acetaminophen OE Capsule Dissolution Surfactant Impact (in Water)12CTAB and Tween-80 somewhat delays the capsule openingSDS: high capsule-to-capsule variability However, all conditions release >85% in 10 minutes

Full release (>85%) within 10 minutesUSP Dissolution Workshop, 2014

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Acetaminophen OE Capsule Dissolution Surfactant Impact (in 0.1N HCl)13Surfactants do NOT slow down the drug release in 0.1N HCLCTAB and POE show slightly faster drug release rate (Very low gelatin dissolution rate in 0.5% SDS/HCl does not impact the drug release from OE Capsules see slide #15)

Full release (>85%) within 10 minutesUSP Dissolution Workshop, 2014

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Acetaminophen OE Capsule Dissolution Surfactant Impact (in pH 6.8 Phosphate)14CTAB delays the capsule opening (same as in water) SDS shows very high capsule-to-capsule variability, and did not release >85% at 10 minutes (Note - fully released at 15 minutes)

pH 6.8: Only release ~80% at 10 minutes in SDS mediaUSP Dissolution Workshop, 2014

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Acetaminophen OE Capsule Dissolution SDS (at 0.5%) Impact in Different Media15More variable in water and pH 6.8 PhosphateSDS/pH 6.8: did not release >85% at 10 minutes The results may due to gel strength is stronger in water/pH 6.8 buffer.


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Tier-2 Testing Performance Evaluation

Enzymes Information (Currently in USP )17Pepsin: (750,000 Units or less per 1000 mL)Manufacture: American Laboratories Inc.Product: Pepsin, 1:10,000 PowderLot No: 00511010Pepsin Activity: 1:10,400

Pacreatin: (NMT 1750 USP Units of protease activities per 1000 mL)Manufacture: American Laboratories Inc.Product: Pancreatin 8X USP PowderLot No: 52320708Activity: Protease: 8.1X USP (203 USP units/mg) Amylase: 10.2X USP (255 USP units/mg) Lipase: 33.7 USP Units/mgUSP Dissolution Workshop, 2014

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Control of Experiments 18Need to get Reproducible results! (Tighten all variables!)Materials, Equipment, and ApparatusAnalyst TrainingWell Designed Dissolution Procedures Careful Execution of Testing Methods

Need to have Relevant Samples to Verify Method PerformancePrecise operation for generating cross-linked capsule samples, i.e. 2-hour Treatment with FormaldehydePrompt execution of dissolution testing USP Dissolution Workshop, 2014

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Tier-1 vs. Tier-2: Non-cross-linked Capsules19No significant difference after 10 minutes

Q: NLT 80% in 30 min.USP Dissolution Workshop, 2014

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Tier-1, 0.1N HCl: Non-cross-linked Capsule vs. Cross-linked Capsule20Fails Stage-3!

The ~same level of cross-linked capsule samples (i.e. 2-hour treated) were used for all Tier-2 experiments

Q: NLT 80% in 30 min.Fails Stage-3!USP Dissolution Workshop, 2014

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Tier-1, pH 6.8: Non-cross-linked Capsule vs. Cross-linked Capsule21Fails Stage-3!


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Pepsin, 750,000 Units/L22Current 750,000 units/L is equivalent to 16,000,000 FCC units/LFor X-linked capsule (2-hour treated with formaldehyde), Tier-2 result at 30 minutes is 92% ( 6.2%)May Pass S-1 of Tier-2

(Use as Reference)USP Dissolution Workshop, 2014

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Pancreatin, 1750 Units/L23Current 1750 units/L For X-linked capsule (2-hour treated with formaldehyde), Tier-2 result at 30 minutes is 83% ( 10.6%)Will go to Stage-2 of Tier-2


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Finding Equivalent Pancreatin Level to Match Pepsin Performance24Current 1750 units/L (1X) Levels tested: [Units/L]1750 (1X), 2000, 2500, 3500 (2X), and 5250 (3X) For 2000 Units/L, Tier-2 result at 30 minutes is 93% ( 4.0%) May Pass S-1 of Tier-2

1750 Units/L2000 Units/L

5250 Units/L (3X)


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Pancreatin vs. Pepsin Performance251750 Units/L2000 Units/LPepsin, USP Dissolution Workshop, 2014

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Enzymes Information (New for pH 4.5) 26Bromelain:Manufacture: American Laboratories Inc.Product: Bromelain 2400 GDULot No: 55920701-AProteolytic Activity: 2,482 GDU/g

Papain:Manufacture: American Laboratories Inc.Product: Papain Full StrengthLot No: 70310665-BProteolytic Activity: 66,900 USP units/mgUSP Dissolution Workshop, 2014

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Method Development Considerations27Materials / Enzyme Does it work?Equipment, Apparatus, and Analyst Consistent Performance!Enzyme Activity How much to use?Well Controlled Dissolution Procedures Solution Stability


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Tier-1, pH 4.5: Non-cross-linked Capsule vs. Cross-linked Capsule28Fails Stage-3!


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Screening Bromelain at pH 4.5 to Match Pepsin Performance29Starting point: 0.5 g/L (i.e. ~1250 GDU/L) Levels tested: [GDU/L]1250, 500, 100, 50, 40, 30, and 25 GDU/L For 30 GDU/L, Tier-2 result at 30 minutes is 91% ( 7.0%) Will Pass S-2 of Tier-2

Very Effective!

25 GDU/L30 GDU/L100 GDU/LUSP Dissolution Workshop, 2014

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Bromelain vs. Pepsin Performance30

30 GDU/L25 GDU/LPepsin, USP Dissolution Workshop, 2014

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Screening Papain at pH 4.5 to Match Pepsin Performance31Starting point: 9 mg/L (i.e. ~600,000 U/L) Levels tested: [KU/L]600, 550, 525, and 500 KU/L Very small amount of Papain Used:


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Screening Papain at pH 4.5 to Match Pepsin Performance (cont.)32The results seem more variable than BromelainFor 550 KU/L, Tier-2 result at 30 minutes is 95% ( 3.0%)For 525 KU/L, Tier-2 result at 30 minutes is 85% ( 9.9%) Will go to Stage-2 of Tier-2

525 KU/L550 KU/LUSP Dissolution Workshop, 2014

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Papain vs. Pepsin Performance33

550 KU/L525 KU/LPepsin, USP Dissolution Workshop, 2014

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Stability of Papain Medium at 550,000 Units/L34X-linked Capsule / Tier-2 Testing: Levels = 550 KU/L After 7 hours, Tier-2 result at 30 minutes is 78% ( 15.3%) May Fail the Tier-2


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Stability of Papain Medium at 525,000 Units/L35X-linked Capsule / Tier-2 Testing: Levels = 525 KU/L Up to 4 hours, the dissolution rate did not slow downOverall, it shows high variability from run-to-run using Papain at 550 KU/L and 525 KU/L


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Stability of Bromelain Medium at 30 GDU/L36X-linked Capsule / Tier-2 Testing: Levels = 30 GDU/L The dissolution rate are very consistent up to 4 hoursAfter 7 hours, Tier-2 result at 30 minutes is 70% ( 9.6%) May Fail the Tier-2


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Solution Stability of Enzyme Media37Enzyme activity will drop over time in solutionFrom the observations of Bromelain and Papain media, it suggests that the dissolution run should start within 4 hours after the media is made. The media is no longer suitable after 7 hours.Pepsin and Pancreatin was not been tested for solution stability, but the same concern for solution stability should be considered. Freshly prepared solution Use within 24 hours rule may not apply to Tier-2 dissolution media


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Summary: Recommended Levels of these four EnzymesRecommended levels of Enzymes:Pepsin: 750,000 Units/L (), i.e. 16,000,000 FCC units/LPancreatin: 2000 Units/LBromelain: 30 GDU/LPapain: 550,000 Units/L

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Summary and Next Steps The gelatin dissolves faster in 0.1N HCl than pH 4.5 & pH 6.8SDS may interact with gelatin and show more variable results. The impact may not be significant for fast dissolving formulationsPepsin in 0.1N HCl is used as the reference, and identified the appropriate levels for the other three enzymes

Next Steps:Confirm these experiment results from other labsDetermine working pH ranges for each enzymesUnderstand the enzyme activity, and make sure to be consistent from various suppliers

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The design, study conduct, and financial support for the study were provided by Abbvie. Abbvie participated in the interpretation of data, review, and approval of the presentation.Abbvie is the sole source of funding for the related studies in this presentation. No other entity has provided any funding for the related studies in this presentation.Disclosures40USP Dissolution Workshop, 2014

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AcknowledgementDr. Jian-Hwa Han is employed at Abbvie. Dr. Han was the primary investigator for this study.Mr. Daniel Bonilla is employed at Abbvie. Mr. Bonilla provided technical assistance for this study.Ms. Susan George and Dr. Paul D. Curry, Jr. are employed at Abbvie and contributed scientific discussions and reviewed the presentation materials.

Mr. Thomas Langdon of American Laboratories, Inc. provided enzymes for this study, and the technical information regarding materials.41USP Dissolution Workshop, 2014

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Q&A

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Dissolution by FO-UV System44System 1: Distek Opt-Diss FO-UV Dissolution SystemSystem 2: Sotax with Rainbow FO-UV SystemAdvantage: Direct detection with details profiles (and w/o Sampling errors) Apparatus 2 @ 50 rpmSamplesHard Gelatin ShellTylenol TabletOE Tylenol SampleCross-linked OE Tylenol Sample


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Comparison of Gelatin Dissolution Time in Various Media45Note In general, the capsule opens within 2 minutes in 0.1N HCl.


45Note - The relationship between drug release and amount gelatin dissolved is case-by-case depending on the formulation

Comparison of Acetaminophen Dissolution Time: Tablet vs. OE Capsule in Various Media 46The Tablet full releases the drug within 3 minutes (> 90% for all media tested)The OE Capsule releases >85% drug within 10 minutes for all conditions tested


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Disintegration Evaluation:Another Look from Different Hydrodynamics47Bromelain @30 GDU/L and Papain @525 KU/L have much longer disintegration time than Pepsin@6X works well (6 capsules in 1 beaker)

Water can not open the X-linked capsules within 15 minutesPancreatin @1750 units/L is weaker than SGF and Pepsin (similar to dissolution results)


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dissolution testing_usp workshop_2014 final

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