HPMC Capsule_USP Workshop_2014 Final

Subhead Calibri 14pt, White

Evaluating the Use of HPMC Capsule in Drug Product Development

USP Workshop on Dissolution Testing of CapsulesMarch 25, 2014

Alex DeacKevin EnghJian-Hwa Han*Bill Huang

Presentation Outline• Objective

• Background

• Key Areas of Investigation

• Results and Discussion- In Vitro Evaluation- Manufacturability Evaluation

- Brittleness Evaluation- Cost Consideration

• Conclusion and Recommendation

USP Dissolution Workshop, 2014 2

Motivation and Objective

Motivation:

- Limited prior knowledge and experience in using HPMC capsules for drug product development.

Objective:

- Evaluate physicochemical properties of HPMC capsules in terms of in-vitro drug release performance and manufacturability against commonly used Hard Gelatin Capsule (HGC); identify limitations, if any.


Background:Main Issues of Hard Gelatin CapsulesHigh moisture content (13-15%)1

• Brittle in low RH (<12% LOD = <30% RH environment)• Softening in high RH (>18% LOD = > 70% RH environment)• Risk of using desiccants due to brittleness

Chemical/Physical stability• Cross-linking over time (high temp, RH, API/excipients/impurities)

Other Concerns for Global Product• Animal derived ingredient (Collagen)• BSE/TSE

1. Sherry Ku M., Li, Weiyi. “Performance Qualification of a New Hypromellose Capsule Part I” Capsugel.


Background: HPMC vs. Hard Gelatin Capsules – Pro’s

• Low moisture content (2-7%)~ 13 % to 65% RH environment

• Less hygroscopic (less sensitive to moisture)• Plant derived• No Cross-linking concerns• Suitable for semi-solid matrix and liquid

formulations• Better for functional coating (e.g. Enteric coating)


Background: HPMC vs. Hard Gelatin Capsules – Con’s• Lower film strength at ambient conditions2

• Higher weight variation• Dissolution issues dependent on the gelling agent used3

• Limited knowledge for in vitro performance, stability, and manufacturability

• Fewer available vendors• Risk in switching between vendors due to gelling agents• Higher unit cost

2. Missaghi, S.,Fassihi, R. “Evaluation and Comparison of Physicomechanical Characteristics of Gelatin and Hypromellose Capsules”.

3. “Two Piece Gelatine Capsules”. Qualicaps. March, 2013


Key Areas of Investigation

• Part I: In vitro performance evaluation

• Part II: Manufacturability evaluation

• Part III: Brittleness evaluation

• Part IV: Cost comparison


Part I:In Vitro Drug Release/Dissolution Experimental• Materials:

Other HPMC capsules also evaluated on paper: Vcaps (Capsugel), Embo Caps VG (Suheung), NatureCaps (ACG), K-Caps (Caps Canada)

• Dissolution Media:– Various pH, Ion types, Ion concentration and surfactants

• Dissolution Method: – USP II (paddle) – Continuous FO-UV detection on 6 channels– 900 ml of media– 75 rpm ( up to 30 min), 200 rpm (>30 min)– 37 ºC– N = 6– Sinker Type: QLA #CAPWHT-TR

Brand Name Manufacturer Type Gelling Agents Short NameConi Snap Capsugel Hard Gelatin none HGCVcaps Plus Capsugel HPMC none VC+

Quali-V Qualicap HPMC Carrageenan QV


Research Formulation Composition (for Dissolution Evaluation)

Material PercentModel compound A (Highly soluble in all media used) 4.0

Lactose Monohydrate FastFlo #316 57.5Dibasic Calcium Phosphate, Anhydrous (FUJICALIN SG) 15.0

Avicel PH-102 15.0

Croscarmellose Sodium 5.0

Hydroxypropyl Cellulose, Vis 10%, 300-600 CPS, Extra Fine 3.0

Magnesium Stearate, (Vegetable Grade) 0.5


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Dissolution: pH Effect

Credit to Han, Jian-Hwa H.

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Water pH 4.5

~ pH 1 pH 6.8

Capsule Opening: (Faster) HGC QV VC+ (Slower)USP Dissolution Workshop, 2014 10

Dissolution: Surfactant (SDS, POE and CTAB) EffectDisolution Comparison in Water

0.0

20.0

40.0

60.0

80.0

100.0

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

Time, Min.

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HPMC, VC+ HPMC, QV HGC, Gelatin

Disolution Comparison in 0.5% SDS

0.0

20.0

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0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

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Disolution Comparison in 0.5% CTAB

0.0

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0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

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Disolution Comparison in 0.5% POE10LE

0.0

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0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

Time, Min.

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QV is more sensitive to CTAB

HGC is more sensitive to SDS

CTAB: Cetyl trimethylammonium bromide; SDS: Sodium dodecyl sulfate; POE: polyoxyethylene lauryl ether

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Water SDS

POE CTAB


Dissolution: Ionic Effect (Na+ vs. K +)

Disolution Comparison in pH 6.8 Phosphate

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Disolution Comparison in pH 6.8 Phosphate (K+)

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50 mM Sodium Phosphate 50 mM Potassium Phosphate


Disolution Comparison in Water

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In Water as Reference

Slower opening for QV

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Impact of Ion Type and Ion Concentration on QV Dissolution

Ion Type Effect (@50 mM) “Extreme” Ionic condition

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.00.0

20.0

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QV Capsule Dissolution Comparison in 0.01N HClNa+ vs. K+ vs. Ca++

50 mM NaCl 50 mM KCl 50 mM CaCl20.01N HCl

Time, Min.

%LC

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Na+

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• 50mM KCl• 150mM NaCl/110mM KCl/15mM CaCl2• 300mM NaCl/170mM KCl/30mM CaCl2


Effect of Storage Conditions on VC+ Dissolution: Stability (40ºC/75%RH up to 8 wks)

Capsule 40C/75RH Stability: HPMC VC+ Capsule(Media = 0.01N HCl)

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Time, Min.

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Initial 1 week 2 weeks 4 weeks 6 weeks 8 weeks

Capsule 40C/75RH Stability: Hard Gelatin Capsule(Media = 0.01N HCl)

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Time, Min.%

LC


VC+ VS. HGC

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It is well known that HGC will show slower dissolution profiles when stored at 40ºC/75%RH conditions.

Some slowing down, but no Impact at 30 minutes.


Effect of Storage Condition on QV Dissolution Stability (40ºC/75%RH up to 8 wks)

Capsule 40C/75RH Stability: HPMC QV Capsule(Media = 0.01N HCl)

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Capsule 40C/75RH Stability: Hard Gelatin Capsule(Media = 0.01N HCl)

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QV vs. HGC

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It is well known that HGC will show slower dissolution profiles when stored at 40ºC/75%RH conditions.

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Effect of Storage Condition on Dissolution Stability Under Low RH (~12%) Condition up to 24 Days

0 5 10 15 20 25 30 35 400.0

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Capsule 40C/12RH Stability: Media = 0.01N HCl

VC+ Initial QV Initial HGC Initial VC+ 24 Days

QV 24 Days HGC 24 Days

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No difference after 20 minutes.

USP Dissolution Workshop, 2014

Dissolution: Consistency of HGC Across Different Media

Disolution Comparison - Gelatin HGC Capsule

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0.1N HCl pH 4.5 pH 6.8 (Na+) WaterpH 6.8 (K+) SDS CTAB POE


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Dissolution: Consistency of QV Across Different Media

Disolution Comparison - HPMC QV Capsule

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Dissolution: Consistency of VC+ Across Different Media

Disolution Comparison - HPMC VC+ Capsule

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Case Study 1: Fast IR Formulation

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No difference after 30 minutes.


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Case Study 2: Complicated Formulation - HGC

Potential Spec Point.

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Case Study 2: Complicated Formulation – HPMC/QV

Potential Spec Point?

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Case Study 2: Complicated Formulation – HPMC/VC+

Potential Spec Point???

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Case Study 2: Complicated Formulation (Mean Profiles, N=6)

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Significant Impact to dissolution results.


Part I: In Vitro Drug Release / DissolutionSummary

• Longer capsule opening time observed from HPMC capsules.

• With fast releasing formulation, no major dissolution concerns observed from either HPMC capsule within the normal conditions tested. However, QV is more sensitive to surfactant (e.g. CTAB) and Ions, esp. Potassium at higher concentration.

• Both HPMC capsules showed no significant dissolution change under 40C/75RH open-dish storage.

• No dissolution rate changes observed from storage in low RH for all capsules (i.e. HGC,QV and VC+).

• For more complicated formulations, thorough evaluation may be needed before selecting the capsule.


Part II: Manufacturability Evaluation

- Capsule Weight Variability

- Robustness of encapsulation under normal production condition


Manufacturing: Weight VariabilityCapsule Size Mean (mg) Standard

Deviation (mg) RSD (%)

00 115.26 2.42 2.100 89.06 2.83 3.18

0 (2nd lot) 89.78 2.25 2.501 75.08 2.50 3.332 60.55 2.24 3.694 37.97 1.27 3.35

00 116.73 1.73 1.470 93.55 1.16 1.46

0 (2nd lot) 93.81 1.26 1.341 75.25 1.08 1.522 62.72 0.89 1.294 38.11 0.92 2.17

00 125.47 4.38 3.490 95.28 2.01 2.11

0 (2nd lot) 94.74 0.78 0.821 73.83 0.57 0.772 61.46 1.63 2.654 37.76 0.99 2.62

Quali-V

HGC

Vcap Plus

N = 500 capsuleUSP Dissolution Workshop, 2014 27

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Encapsulator Bosch GKF 1400; Dosing Disk

Speed 1200 capsules per minute

Running time 40 min (50000 caps)/per run

Weight Checker Bosch KKE 1700

Temperature ~20° C

Humidity 19% and 35% RH

Formulation Avicel PH 101

Weight Checker Limits ± 5% target filled weight

Encapsulation Evaluation


CapsuleTotal

Capsules

RejectedBy Weight

(%)

Mean Weight

(mg)

Target Weight

(mg)Weight

RSD

HGC 68930 0.03 339.2 340 0.71

VC+ 49085 0.54 337.7 340 0.95

VC+ 2nd lot 46836 0.31 337.3 340 1.39

QV 49944 0.00 338.2 340 1.03

QV 2nd lot 50190 0.56 335.7 340 1.25

Lot-to-Lot Variation and Performance of Size 0 HPMC Capsules Compared to HGC under 35% RH Condition


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CapsuleTotal

Capsules

RejectedBy Weight

(%)

Mean Weight

(mg)

TargetWeight

(mg)Weight

RSD

HGC 53466 1.38 115.3 115 1.30

VC+ 48750 0.82 114.5 115 1.66

QV 48726 0.11 114.8 115 1.57

Effect of Size 4 Capsules on Rejection Rate and Weight Variation Under 35% RH


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CapsuleTotal

Capsules

RejectedBy Weight

(%)

MeanWeight

(mg)

TargetWeight

(mg)Weight

RSD

HGC 13549 0.01 341.4 340 0.97

VC+ 24731 0.04 340.5 340 1.20

QV 23984 0.00 334.8 340 1.14

Effect of Low Humidity Conditions (19% RH) on Rejection Rate and Weight Variation of Size 0 Capsules

Capsules were left to equilibrate to the 19% RH for 3-4 days


Encapsulation Observations

• No issues regarding rectification, alignment, opening, filling, closing, and ejecting of either HGC or HPMC capsules during encapsulation.

• HPMC capsules had a slightly larger weight RSD than HGC.

• Minimal rejects and lot-to-lot variation observed.

• HGC had a shattered capsule in 19% RH conditions. This could be a potential problem in longer runs. No issues found with the HPMC capsules.


Part II: Manufacturability Evaluation Summary- HGC has an overall better empty capsule weight control

than HPMC capsules, however, both QV and VC+ are still acceptable with the observed variation.

- Both QV and VC+ have demonstrated acceptable manufacturability/robustness under normal and lower RH conditions.

- HPMC capsules also demonstrate better physical and mechanical properties during the encapsulation process as well as upon storage.

- HGC and HPMC capsules are comparable in terms of overall manufacturability.


Part III: Brittleness Evaluation

Method: • Capsules were stored in bottles, one per type of capsule• A set of bottles were stored in desiccators that were

subsequently stored in a chamber with controlled temperature. A second set of capsules were stored at ambient conditions in the lab.

• Samples were removed to perform tests under ambient conditions.

• N=10 capsule per weight drop


Brittleness Evaluation – Impact Tester

Equipment Used: Impact Tester

Hollow tube with a height of ~2 feet through which a weight pellet can be dropped onto a capsule held in place at the bottom of the tube by a capsule holder.

Stainless steel impacter

SGC

Stainless steel insert

Stainless steel base plate

Acrylic socket

Acrylic tube guide

Pin hole / Vent hole

Release Pin

Vent hole

Seam hole


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Part III: Brittleness EvaluationResults and Summary

15 20 25 30 35 40 45 50 550

102030405060708090

100

Capsule Shell Resistance to Impact at ~22 C° and 35-55% RH

Hard GelatinVcap PlusQuali-V

Weight Dropped From 30.25 Inches (g)

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0 10 20 30 40 50 600

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100

Capsule Shell Resistance to Impact at 40°C and 25% RH for 83 Days

Hard GelatinVcap PlusQuali-V

Weight Dropped From 30.25 Inches (g)

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HGC becomes more brittle under hi-temp and low humidity condition over time.


Part III: Cost Evaluation

HGC: ~

HPMC: ~

37USP Dissolution Workshop, 2014

Conclusion and Recommendation- Both HPMC capsules (i.e. QV and VC+) fit for

Oral Drug Development.

- HPMC capsules are generally not recommended due to the cost concerns relative to HGC.

- If HPMC capsule will be used, a thorough evaluation is recommended to make sure the overall performance meets expectations.


• 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.

Disclosures


Acknowledgement• Dr. Jian-Hwa Han is employed at Abbvie. Dr. Han planned and

executed the dissolution experiments for this study.

• Dr. Ye Huang is employed at Abbvie. Dr. Huang was the primary investigator for this study.

• Mr. Alexandru Deac is employed at Abbvie. Mr. Deac was the key formulator for this study.

• Mr. Kevin Engh is employed at Abbvie. Mr. Engh was the process engineer for this study.

• Dr. Gregory K. Webster and Dr. Paul D. Curry, Jr. are employed at Abbvie who contributed to scientific discussions and reviewed the presentation materials.

40USP Dissolution Workshop, 2014

Q&A

Documents

HPMC Capsule_USP Workshop_2014 Final