USP Disso Workshop_Tier 2 Method_JHH 11Jun2012 Final v3
HPMC Capsule_USP Workshop_2014 Final
1. Subhead Calibri 14pt, White
Evaluating the Use of
HPMC Capsule in Drug
Product Development
USP Workshop on Dissolution
Testing of Capsules
March 25, 2014
Alex Deac
Kevin Engh
Jian-Hwa Han*
Bill Huang
2. Presentation Outline
• Objective
• Background
• Key Areas of Investigation
• Results and Discussion
- In Vitro Evaluation
- Manufacturability Evaluation
- Brittleness Evaluation
- Cost Consideration
• Conclusion and Recommendation
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3. 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.
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4. Background:
Main Issues of Hard Gelatin Capsules
High 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.
USP Dissolution Workshop, 2014 4
5. 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)
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6. 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
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7. Key Areas of Investigation
• Part I: In vitro performance evaluation
• Part II: Manufacturability evaluation
• Part III: Brittleness evaluation
• Part IV: Cost comparison
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8. 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 Name
Coni Snap Capsugel Hard Gelatin none HGC
Vcaps Plus Capsugel HPMC none VC+
Quali-V Qualicap HPMC Carrageenan QV
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9. Research Formulation Composition
(for Dissolution Evaluation)
Material Percent
Model compound A (Highly soluble in all
media used)
4.0
Lactose Monohydrate FastFlo #316 57.5
Dibasic 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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11. Dissolution: Surfactant (SDS, POE and CTAB) Effect
Disolution 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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
Disolution Comparison in 0.5% SDS
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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
Disolution Comparison in 0.5% CTAB
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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
Disolution Comparison in 0.5% POE10LE
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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
Credit to Han, Jian-Hwa H.
QV is
more
sensitive
to CTAB
HGC is
more
sensitive
to SDS
CTAB: Cetyl trimethylammonium bromide; SDS: Sodium dodecyl sulfate; POE: polyoxyethylene lauryl ether
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
Water SDS
POE CTAB
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12. Dissolution: Ionic Effect (Na+ vs. K +)
Disolution Comparison in pH 6.8 Phosphate
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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
Disolution Comparison in pH 6.8 Phosphate (K+)
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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
50 mM Sodium Phosphate 50 mM Potassium Phosphate
Credit to Han, Jian-Hwa H.
Disolution 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.
%LC
HPMC, VC+ HPMC, QV HGC, Gelatin
In Water as Reference
Slower
opening for
QV
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
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13. Impact of Ion Type and Ion Concentration
on QV Dissolution
Ion Type Effect (@50 mM) “Extreme” Ionic condition
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
%LC
Time, Min.
QV Capsule Dissolution Comparison in 0.01N HCl
Na+ vs. K+ vs. Ca++
50 mM NaCl 50 mM KCl
50 mM CaCl2 0.01N HCl
FullRecovery
(@200rpm)
Na+
K+
Ca++
• 50mM KCl
• 150mM NaCl/110mM KCl/15mM CaCl2
• 300mM NaCl/170mM KCl/30mM CaCl2
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14. 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)
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25 30 35 40
Time, Min.
%LC
Initial 1 week 2 weeks 4 weeks 6 weeks 8 weeks
Capsule 40C/75RH Stability: Hard Gelatin Capsule
(Media = 0.01N HCl)
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25 30 35 40
Time, Min.
%LC
Initial 1 week 2 weeks 4 weeks 6 weeks 8 weeks
VC+ VS. HGC
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
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.
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15. 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)
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25 30 35 40
Time, Min.
%LC
Initial 1 week 2 weeks 4 weeks 6 weeks 8 weeks
Capsule 40C/75RH Stability: Hard Gelatin Capsule
(Media = 0.01N HCl)
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25 30 35 40
Time, Min.
%LC
Initial 1 week 2 weeks 4 weeks 6 weeks 8 weeks
QV vs. HGC
FullRecovery
(@200rpm)
FullRecovery
(@200rpm)
No Impact.
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It is well known that HGC will show slower dissolution profiles when stored
at 40ºC/75%RH conditions.
16. 16
Effect of Storage Condition on Dissolution Stability
Under Low RH (~12%) Condition up to 24 Days
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25 30 35 40
%LC
Time, Min.
Capsule 40C/12RH Stability: Media = 0.01N HCl
VC+ Initial QV Initial HGC Initial
VC+ 24 Days QV 24 Days HGC 24 Days
FullRecovery
(@200rpm)
No difference
after 20 minutes.
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17. Dissolution: Consistency of HGC Across Different Media
Disolution Comparison - Gelatin HGC Capsule
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.
%LC
0.1N HCl pH 4.5 pH 6.8 (Na+) Water
pH 6.8 (K+) SDS CTAB POE
Credit to Han, Jian-Hwa H.
FullRecovery
(@200rpm)
SDS
CTAB
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18. Dissolution: Consistency of QV Across Different Media
Disolution Comparison - HPMC QV Capsule
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.
%LC
0.1N HCl pH 4.5 pH 6.8 (Na+) Water
pH 6.8 (K+) SDS CTAB POE
Credit to Han, Jian-Hwa H.
FullRecovery
(@200rpm)
CTAB
K+
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19. Dissolution: Consistency of VC+ Across Different Media
Disolution Comparison - HPMC VC+ Capsule
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.
%LC
0.1N HCl pH 4.5 pH 6.8 (Na+) Water
pH 6.8 (K+) SDS CTAB POE
Credit to Han, Jian-Hwa H.
FullRecovery
(@200rpm)
SDS
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20. Case Study 1:
Fast IR Formulation
20
No difference
after 30 minutes.
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21. 21
Case Study 2:
Complicated Formulation - HGC
Potential Spec Point.
FullRecovery
(@200rpm)
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22. 22
Case Study 2:
Complicated Formulation – HPMC/QV
Potential
Spec Point?
FullRecovery
(@200rpm)
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23. 23
Case Study 2:
Complicated Formulation – HPMC/VC+
Potential Spec
Point???
FullRecovery
(@200rpm)
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24. Case Study 2:
Complicated Formulation (Mean Profiles, N=6)
24
Significant Impact to
dissolution results.
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25. Part I: In Vitro Drug Release / Dissolution
Summary
• 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.
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26. Part II: Manufacturability Evaluation
- Capsule Weight Variability
- Robustness of encapsulation under normal
production condition
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32. 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.
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33. 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.
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34. 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
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35. 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.
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36. 36
Part III: Brittleness Evaluation
Results and Summary
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60
PercentBrokenoutof10
Weight Dropped From 30.25 Inches (g)
Capsule Shell Resistance to Impact at ~22 C° and 35-55% RH
Hard Gelatin
Vcap Plus
Quali-V
0
20
40
60
80
100
0 10 20 30 40 50 60
PercentBrokenoutof10
Weight Dropped From 30.25 Inches (g)
Capsule Shell Resistance to Impact at 40°C and 25% RH for 83 Days
Hard Gelatin
Vcap Plus
Quali-V
HGC becomes more brittle under hi-temp and low humidity condition over
time.
USP Dissolution Workshop, 2014
38. 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.
USP Dissolution Workshop, 2014 38
39. • 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
USP Dissolution Workshop, 2014 39
40. 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
