"Innovating in Advanced

Softgel Technologies"

Softigel by Procaps

Analytical challenges related to Softgel testing.

Speaker: Diego Monterroza H. M,Sc
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@SoftigelProcaps

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About Procaps
Latin America's largest softgel producer with facilities in
Brazil, Colombia and Venezuela, and exports reaching
more than 42 countries worldwide.
Deep knowledge in gelatin formulation and an
impressive scientific expertise in softgel technologies.
Specialized in innovative softgel associated technologies
such as UnigelTM, VersagelsTM, G- tabsTM & GummygelsTM.
We cater to multinational pharmaceutical clients,
including Pfizer, Glaxo Smith Kline, Sanofi-Aventis,
Behringer Ingelheim, and Bayer among others.

Content
1. Introduction
2. Dynamic equilibrium of soft capsules
3. Cross-Linking
4. Recommended additional tests during stability
5. Conclusions

Soft capsules are a single-unit solid dosage form, consisting of a liquid or

semisolid fill enveloped by one-piece hermetically sealed elastic outer shell.

Hydrophillic
Lipophillic
Mixed Matrix

Tablets!
Capsules!
Pellets!
Suspension
Solution
Emulsion

Gelatin/non-Gelatin
Plasticizers
Water

VersagelsTM
Enteric Coating
FILL
Opacifiers
Flavors
Colors (one or two)

Manufacturing workflow.

FILL

Fill preparation

FILL PUMP

LEADS

FEEDER ROLLS

Gelatin mass preparation

INJECTION WEDGE

RIBBON GUIDES

RIBBON

Encapsulation
TUBE

DIE

DIE

CHUTE

Drying

SPREADER
BOX
DRUM

NET
OIL ROLLS

Finishing

CAPSULE
CONVEYOR

Schematic drawing of a rotary-die soft gelatin capsule filler (R.P. Scherer: Detroit, MI)

FILL TANK

Dynamic Equilibrium
of soft capsules

Dynamic Equilibrium of soft capsules

Expected migration for several SGCs formulations:

Primary Drying
Immediately after
encapsulation

Secondary Drying
After secondary drying
(Equilibrium)

After primary drying

PEG Fill
-1,2%

PEG Fill
-16%

PEG Fill
-8%
3

Mixed MC
Triglycerides
Fill -0,15%

Mixed MC
Triglycerides
Fill -4,6%

Mixed MC
Triglycerides
Fill -2,4%
3

MCT/LCT
Fill -0,1%

MCT/LCT
Fill -0,1%
3

MCT/LCT
Fill -0,1%

Fill content is diluted

One of the major challenges in the
development of soft capsules is that the
system is very dynamic in terms of physical
migration or even chemical interactions.

Review Soft Gelatin Capsules (Softgels) Rampurna Prasad Gullapalli Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, California 94080

Dynamic Equilibrium of soft capsules

If formulation or process is not well-done, migration can continue through shelf life:

Atmospheric Moisture
k1

Gelatin

k3

k2

k4

k5

Magnitude of each k depends on several

factors: formulation, manufacturing process
and storage conditions.

k6

API(s) + Liquid Content

Pla k8
stic
izers
(s)
k9

k10
Water

k11

k12

e
Dy

k13

Those migration, if not controlled, could

affect both physical and chemical stability
of the finished product.

Dynamic Equilibrium of soft capsules

Case Study 1: Lipophilic product, no dilution of the fill content.

MCT/LCT
Fill -0,1%

MCT/LCT
Fill -0,1%
3

Assay Through Stability

Net Weight Through Stability

104

525,0

102

100,5

100

99,7

498,4

502,6

99,6

98

501,7

505,0

mg

% of label

MCT/LCT
Fill -0,1%

96

95,7

485,0

478,0

465,0

94
445,0

92
90

Month
Assay Through Stability

425,0

Month
Net Weight Through Stability

Dynamic Equilibrium of soft capsules

Case Study 1: Lipophilic product, no dilution of the fill content.
Weight Variation for OOT Value (95.7%)

Corrected Weight Variation

Capsule No.

Total Weight
(mg)

Shell Weight
(mg)

Net Weight (mg)

Capsule No.

Total Weight
(mg)

Shell Weight
(mg)

Net Weight
(mg)

804.0

301.9

502.1

808.4

333.7

474.7

816.6

316.5

500.1

822.0

337.8

484.2

798.8

298.9

499.9

800.6

329.6

471.0

844.3

334.6

509.7

824.6

355.7

468.9

823.4

322.6

500.8

833.6

335.8

497.8

814.2

314.7

499.5

832.1

365.8

466.3

809.8

310.9

498.9

810.5

333.3

477.2

821.0

323.6

497.4

834.6

339.9

494.7

835.6

330.0

505.6

833.2

345.7

487.5

10

835.3

324.6

510.7

10

823.4

365.8

457.6

Average

820.3

317.8

502.5

Average

822.3

344.3

478.0

MIN

798.8

298.9

497.4

MIN

800.6

329.6

457.6

MAX

844.3

334.6

510.7

MAX

834.6

365.8

497.8

SD

14.66

11.56

4.62

SD

12.04

13.50

12.89

RSD

1.8

3.6

0.9

RSD

1.5

3.9

2.7

Dynamic Equilibrium of soft capsules

Case Study 1: Lipophilic product, no dilution of the fill content.

Assay Through Syability

104

% of label

102

Normally, glycerin is
used as a plasticizer for
this formulations and it
is very hygroscopic.

100,6

100,5
99,7

100

99,3

99,6
98
96
95,7

Including OOT Result at Month 3

94

Corrected Month 3 Result

92
90

4
Month

Dynamic Equilibrium of soft capsules

Case Study 2: Hydrophilic Product, dilution of the fill content.

PEG Fill
-1,2%

PEG Fill
-16%

PEG Fill
-8%
3

METHOD 1: weighing the fill content from the capsules, testing,

and calculating Assay based on theoretical weight variation.
METHOD 2: weighing the fill content from the capsules, testing
and calculating Assay based on the actual weight variation at
each sampling time.
METHOD 3: using whole capsules to prepare Assay samples.
No correction by weight.

Dynamic Equilibrium of soft capsules

Case Study 2: Hydrophilic Product, dilution of the fill content.

Month

Method 1

Method 2

Method 3

96.9 (0.3)

99.8 (0.5)

101.3 (1.2)

96.5 (0.6)

99.2 (0.6)

99.6 (1.3)

95.1 (0.5)

99.5 (0.5)

103.2 (1.2)

94.0 (1.2)

98.9 (0.3)

101.7 (2.1)

Effect of water migration into the fill.

Water migration does not continue through stability.
Results affected by uniformity of dosage
We can test the whole capsules but variability affects assay, but not CU.

Cross-Linking

Cross-Linking
Depending on the involved reactions,
cross-linking is evidenced on different part of the capsules:

Shell

Fill Content

Self

g
n
i
k
in
L
s
s
Cro

Fill Content

Gelatin shell becomes

insoluble by exposure
to T and RH

Fill Content

Insoluble membrane
between fill and shell
(PELLICLE)

Chem
ic
Cros ally Indu
s-Lin
c
king ed

Both types of cross-linking can occur at the same time!

Cross-Linking

PELLICLES

Source: USP Workshop, Maryland 2014.

STICKY MASS

It is well known the affection on both desintegration

and dissolution due to cross-linking.
Dissolution Profiles at Time Zero and after 1
month at accelerated conditions

Cross-Linking

Considerations

110
100

90

% Dissolved

90

86

80
70

56

60
50

S1-Initial
S2-Initial
S3-Initial
S1-1 Month
S2-1 Month
S3-1 Month

53

40
30

23

20
10
0

10

15

20

25

30

35

Time (minutes)

40

45

50

Pepsin is only active until pH 4.o,

not up to pH 6.8
Pepsin activity method and units
Methods were water is the media
What to do with pHs lower than 6.8
and higher than 4.0
What to do if surfactant denatures
enzymes
Using enzymes and regulatory
considerations

Recommended Additional
Tests During Stability

Recommended Additional
Tests During Stability
Weight variation, monitoring
total, shell and net weights.
Shell moisture content.
Fill content moisture.
Rupture time/Disintegration.
Drug substance migration into
the shell.
Shell hardness.
Blooming.

Conclusions

Conclusions
Soft gelatin capsule is a unique dosage
form where dynamic equilibrium affect both
shell and fill composition.
Final equilibrium should be reached after
drying, but depends on formulation and/or
process, it can continue through shelf-life.
Analytical approaches need to take into
account migration phenomena, in order to
avoid either low or high variable results.
According to the approach, strategy for
validation need to be adjusted, in order to
actually verify the capabilities of the
proposed method for the intended purpose.

Why Softigel by Procaps?

First Latin American softgel facilities approved by FDA and MHRA.

Latin America's largest softgel encapsulator

Experience with more than

500

36+Years of experience
243+

softgel formulations

8+

Products in Softgels and associated

techs launched during 2013

Leading softgel
technologies

11

billion doses of
annual capacity

Partner with top global pharma players, generic companies

in High Regulated Markets, Start-up companies; among many others.

Knowlege is a critical component in all of our products

Developing with the end in mind, we deliver robust formulations,
taking into account the safety and efficacy of your drug product.

The best and unique option

for overcoming challenges when
formulating low solubility and/or
low permeability APIs.

Versatile technology
that provides compatibility with
high pH formulations and a broader
range of fill excipients.

Gelatin coated tablets,

the best way of preventing
counterfeiting and masking
unpleasant tastes and odors.

The only technique available

for fixed dose combinations which
incorporates the benefits of the soft
gelatin capsule dosage form.

A new solution in chewable

softgels with attractive and
pleasant flavors offering a great
number of nutritional benefits

Gummies with special formulations

offering consumers a tastier, more
pleasant way of taking vitamins
and supplements.

@SoftigelProcaps

Follow us

Post and share

your comments
under the hashtags

#cphiww
#speakerscorner

Softigel by Procaps
Softigel by Procaps
Download our app
Softigel by Procaps
Gummy Gels by Procaps

www.softigel.com

THANK YOU!

"Innovating in Advanced
Softgel Technologies"