Launch of our new Titanium Dioxide Alternative

The ideal morphology and particle size
for enhanced opacity in tablet coating
Parteck® TA (Calcium carbonate)
Emprove® Essential
TITANIUM
DIOXIDE
ALTERNATIVE
Launch of our new

Launch of Parteck® TA excipient
Potential ban of TiO2 as drug colorant in EU
2
The European Commission has adopted Regulation (EU)
2022/63 withdrawing the authorization to use the food
additive titanium dioxide in foods and dietary
supplements. The ban has become effective in Aug 2022.
TiO2 in medicines: remains for the time being on the list of
authorized color additives. The Commission is to re-evaluate
the situation by Feb 2025 based on an updated EMA
assessment.
Titanium dioxide (TiO2) is
extensively used in solid dosage
forms as an opacifier and
colorant in medicine due to
multiple functionalities.
91,000
Medications in the EU
could be affected by a ban
“… a clear sign that the pharmaceutical
industry should make any possible
efforts to accelerate the research and
development of alternatives to replace
titanium dioxide in both new and
already authorized products…”
EU
Commission
EU Commission, Jan 2022
Source: EMA, Final Feedback, Sep 2021

Scientific basis for the ban of TiO2
Food and nutritional supplements in EU
3
This conclusion was reached using all available evidence along with
all the uncertainties, in particular the fact that a genotoxicity
concern could not be ruled out. EFSA did not conclude that E171
is genotoxic, but it was not able to establish a maximum Acceptable
Daily Intake (ADI) for this food additive, in particular due to possible
concerns with respect to genotoxicity, and thus concluded that the
safety of the product cannot be confirmed.
This assessment also took into account new studies performed with
titanium dioxide nanoparticles. Almost 10,000 different studies were
identified, which have been individually screened and, when
relevant, taken into account in the safety assessment of E 171.
Source: Re-evaluation (europa.eu)
EFSA OPINION
on titanium dioxide (E171), published on 6 May 2021:
INFO
Genotoxicity: ability for
a substance or any other
toxic agent to damage DNA,
the genetic material of cells,
which may in turn, as a
possible consequence, lead
to cancer.
The European Food Safety Authority (EFSA) concluded
that E171 can no longer be considered as safe when
used as food additive.

Intro
Physical Properties
Color Measurements
2
0
3
0
Application in Tablet Film Coatings
4
0
AGENDA
1
0
4

Multi-compendial
Compliant with Ph Eur, BP, USP, E170,
FCC; GRAS
CaCO3: The only other white
colorant authorized for the coloring
of drugs in the EU
Enhanced opacity and coverage
due to tailored particle size distribution
and unique morphology
Meeting regulatory trends with our titanium dioxide alternative
Appealing and uniform tablet finishing
Calcium carbonate (CaCO3)
precipitated; an off-white mineral and
nature-identical pigment with unique
morphology precisely developed to meet
the needs for a suitable TiO2 alternative
Emprove® documentation
facilitates qualification, risk assessment,
and process optimization
Excellent compatibility
with HPMC and
PVA film coatings
Achieve best opacity results with our
film coating agent Parteck® COAT
5
High process efficiency
due to lower viscosity of the
spraying liquid
Discover our new
Parteck® TA
Emprove®
Essential
Art. no. 124069

Your way to flexibility
2 high performers for your film coating
6
• Article Number:
124069
• Packaging sizes:
1 kg in PE bottle
25 kg in PE bag in carton
• Particle size:
d50: 2-6 µm
d90: 7-15 µm
• Article Number:
141517
• Packaging sizes:
1 kg in PE bottle
25 kg in PE bag in carton
• Particle size:
d50: 180 - 260 µm
d90: 300 - 700 µm
Parteck® COAT
(Polyvinyl alcohol) EMPROVE®
ESSENTIAL Ph Eur, ChP,
JPE, USP
Parteck® TA
(Calcium carbonate)
EMPROVE® ESSENTIAL
Ph Eur, BP, USP, E170, FCC
PIGMENT COATING
AGENT
FILM

Closer look at Parteck® TA excipient
SEM pictures and morphology
8
5 10 15 20 25 30 35 40 45 50 55 60
Parteck®
TA
°2Theta
Offset
ENHANCED
OPACITY
• Unique particle shapes
in narrow range of
particle sizes
• Defined crystalline
structure
Specific patttern of crystalline Parteck® TA (calcium
carbonate) in diffractogram measured by powder X-ray
diffraction (PXRD, STOE GmbH); parameters: 40kV, 40 mA
Ground range images of Parteck® TA
in 2 resolutions taken by scanning
electron microscopy (SEM)
CaCO3
(Calcit)
enabled by

Sample Parteck®
TA C1 C2 C3 C4
Particle size /d50 (µm) 3 2 1 19 22
Particle size /d90 (µm) 8 5 5 39 44
BET spec. surface (m²/g) 3.8 12.0 10.8 0.3 0.3
Note: The presented particle size distribution (PSD) data are related to one lot
of Parteck® TA and are not claiming any PSD specification for this product.
Equipment:
Malvern Mastersizer 2000
Particle size distribution (PSD):
Parteck® TA excipient vs. benchmarks
The ideal particle size for an enhanced brightness
9
Inorganic pigments
selectively absorb and
scatter the incident light.
The smaller the particles,
the smoother the surface.
INFO
RESULTS:
C1-C4: calcium carbonate products from other suppliers
Parteck® TA features an ideal
particle size distribution
enabling enhanced opacity.

Parteck® TA excipient vs. benchmarks
Low water uptake assures the performance
10
C1-C4: calcium carbonate products from other suppliers
Equipment: Dynamic vapor sorption (DVS) isotherms
Water uptake properties
In comparison to the benchmark samples C1-C4, Parteck® TA
shows a low water uptake enabling a good stability

White pigments and optical principles
Brightness is the ability to scatter incident light
12
Optical principle in the
interaction of visible light
with a white pigment
Pigment
Refraction
index
Titanium dioxide 2.49
Zinc oxide 2.0
Calcium carbonate
(Parteck® TA excipient)
1.66
Refractive indices of white pigments
Source: Alternatives to titanium dioxide in tablet coating; Radke, Wiedey, Kleinbudde (2021),
Pharmaceutical Development and Technology, 26:9, 989-999
Titanium dioxide
• brightest, whitest
pigment available
• due to its high refractive
index, it effectively
scatters light and
provides highest opacity
and coverage for a
coating
The role of the
refraction index
of a pigment:
A lower refractive
index requires a
higher weight gain
to scatter light to
the required degree.
Next best alternative:
Calcium carbonate
• only other white colorant
approved as drug colorant in EU
• offers opacifying properties
Pigment
Refraction
index
Dibasic calcium phosphate 1.55
Magnesium carbonate 1.54
Microcrystalline
cellulose
1.46

The CIELab or CIE L* a* b*:
quantitative measurement and
relationship of colors
Colorimeric values:
L axis: lightness
a axis: red-green values
b axis: yellow-blue values
• Identification of any color
• Quantification of color differences:
INFO
Intro to color measurements
The CIELab color system
13
The CIELab 3D space:
The opponent color model
= (∆𝐋)𝟐+(∆𝐚)𝟐+(∆𝐛)𝟐
L = 100
white
yellow
+ b
blue
- b
L = 0
black
red
+ a
green
- a
∆𝑬𝒂𝒃
∗

Parteck
®
TA
TiO
2
Pre-screening with black and white drawdown cards
Visual comparison of films with TiO2 and Parteck® TA
14
Basis formulation: Parteck® COAT solution (20%)
Thickness of the film: 0.08-0.15 mm
Card film applicator: Moeller, CI-K3-125-M
Higher concentrations required
with calcium carbonate to
achieve a comparable coverage
Y: Reflectance of the incident light
Opacity (%) =
Y black card
Y white card
* 100
Stepwise increase of solid content in 20% Parteck® Coat solution
Opacity is the hiding power
of a pigment: The value is
100% in the case of a
complete coverage of the
black color card.
→ No difference can be
seen between the film
material over black and
white substrates
INFO
Note: it depends on the pre-
coloring and not every tablet
needs high opacity
10% 20% 30% 40%

APPLICATION
IN TABLET
COATINGS
04

Simulation of pre-colored tablet formulations
Tablet cores for film coating trials
16
Equipment/Methods:
 lab-scale coater of Vector Corporation (A Freund Group company) LDCS
 CIE Lab measurement: Konica Minolta Spectrophotometer CM-700d
Tablets cores:
Standard formulation: 98 % mannitol,
1.5 % magnesium stearate, 0.5 % red iron oxide
Red iron oxide used to demonstrate the opacity
performance
Convex tablets: 500 mg weight, 11 mm diameter
Tableting performed with tablet press Fette 1200i
(Fette Compacting GmbH)
Coating suspension:
10% talcum, 20% triethyl citrate; HPMC and Parteck®
COAT (PVA) amount was adapted to individual
formulation

Technical evaluation
Parteck® TA vs. titanium dioxide in PVA film coating
17
17
9 % Solid in Coating
Suspension
30 % CaCO3
3 % Weight Gain
Suspension
30 % CaCO3
5 % Weight Gain
Suspension
40 % CaCO3
5 % Weight Gain
Suspension
40 % TiO2
5 % Weight Gain
Suspension
40 % CaCO3
8 % Weight Gain
Suspension
40 % CaCO3
~20 % Weight Gain
Based on:
98 % Mannitol
0.5 % Iron oxide
1.5 % Magnesium stearate based
Raw tablets
(uncoated):
Increasing solid content and weight gain
Comparable
formulation
TiO
2
Parteck
®
TA
Our
recommendation:
A weight gain of 5 % - 8 %
is suitable for most of
the tablets

Close view on coating layer with SEM
Homogeneous distribution of Parteck® TA in the coating
18
Coated Tablet with
TiO2
Coating
Formulations:
• 20 % solid in
coating dispersion
• 40 % pigment
• 5 % weight gain
Coated Tablet with
Parteck® TA
Cross section SEM image Cross section SEM image
Ground range SEM image Ground range SEM image
D1-D5: thickness of coating layers (µm)

Comparable
formulation
Galenical parameters of tablets with PVA film coating
Parteck® TA excipient in comparison to titanium dioxide
19
 Overall, the
galenical values
are in a similar
range
 No effect on tablet
performance
expected
PVA coating with
Parteck® TA vs. TiO2
(5% WG):
Overview Parameter
Weight before
coating (mg)
Weight after
coating (mg)
Friability
(%)
Hardness
(N)
Disintegration
time (sec)
Core
98% mannitol
0.5% iron oxide
1.5% magnesium stearate
500 / 0.29 266 325
Parteck®
TA
30% Parteck® TA
3% weight gain
500 514 0.01 353 393
30% Parteck® TA
5% weight gain
500 527 0.01 304 483
40% Parteck® TA
5% weight gain
500 527 0.01 334 493
40% Parteck® TA
8% weight gain
500 543 0.01 326 536
Exemplary maximum loaded
40% Parteck® TA
~20% weight gain
500 611 0.0 326 643
TiO2
40% TiO2
5% weight gain
500 527 0. 01 314 429
Film coating formulation based on Parteck® COAT

CIElab values of coated tablets in dependence of increasing
weight gains (WG) of Parteck® TA excipient vs. TiO2
20
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Raw cores 30% Parteck® TA
3% weight gain
30% Parteck® TA
5% weight gain
40% Parteck® TA
5% weight gain
40% TiO2
5% weight gain
40% Parteck® TA
8% weight gain
40% Parteck® TA
20% weight gain
L*
a*und
b*
a* b* L*
• 5% WG: good results
• 8% WG: minor increase
• 20% WG: limit for study set-up
*Raw tablet cores: high L values caused
by reflection effects on the surface
Impact of weight gain
on lightness of coated
tablets (L value):
Film coating formulation based on
Parteck® COAT solution
Raw cores 30% Parteck® TA
3% weight gain
30% Parteck® TA
5% weight gain
40% Parteck® TA
5% weight gain
40% TiO2
5% weight gain
40% Parteck® TA
8% weight gain
40% Parteck® TA
20% weight gain

Color Measurements of coated tablets with Parteck® TA excipient
Results of Parteck® TA in the range of top products
21
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Core tablets Parteck® TA C1 C2 C3 C4 Titanium dioxide
L*
a*
and
b*
a* b* L*
Film coating formulation:
• Parteck® COAT solution (20%)
• pigment (40%)
• weight gain (8%)
Parteck® TA shows excellent
lightness represented by L values
Core tablets Parteck® TA C1 C2 C3 C4 Titanium dioxide
C1-C4: calcium carbonate products
from other suppliers

0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
L*
a* b* L*
PVA
PVA
PVA
PVA
PVA
HPMC HPMC
HPMC HPMC HPMC
40 % Polymer
20 % Plasticizer
30 % CaCO3
10 % Anti-tacking Agent
30 % Polymer
20 % Plasticizer
40 % CaCO3
10 % Anti-tacking Agent
CIElab values: comparison of tablets coated with PVA and HPMC
Excellent compatibility of Parteck® TA excipient with both films
22
Coating
formula
a*
and
b*
Enhanced opacity can be achieved in combination
with our PVA-based Parteck® COAT
Raw
tablets
3 % Weight gain
9 % Solid Content
5 % Weight gain
15 % Solid Content
5 % Weight gain
20 % Solid Content
8 % Weight gain
20 % Solid Content
8 % Weight gain
30 % Solid Content

Viscosity of coating solutions with Parteck® TA vs. TiO2
Lower viscosity enables high process efficiency
23
Sample Ingredients Dyn. Viscosity (mPa·s)
Basic 6 % Parteck® COAT Solution 10
1 Parteck® COAT + 4.5 % Parteck® TA 13
2 Parteck® COAT + 8.0 % Parteck® TA 19
3 Parteck® COAT + 8.0 % TiO2 39
Basic 6 % HPMC Solution 41
4 HPMC + 4.5 % Parteck® TA 78
5 HPMC + 8.0 % Parteck® TA 91
6 HPMC + 8.0 % TiO2 114
Formulation of the coating solutions 1-6:
polymer (6%), triethyl citrate (3-4%), talc (1.5-2.0 %), pigment (4.5-8.0 %)
• In comparison to HPMC, the
combination with Parteck®
COAT leads to a significantly
lower viscosity
significantly lower influence on
viscosity of coating solutions
than TiO2
Rotating plate viscosimeter: Thermo-Fisher / Haake Mars Rheo 60 Measurement P25/Ti Gap: 0.100 mm CR;
ɣ̇ 100.0 1/s; t 60,00 s; T 20.00 °C
Parteck® TA excipient:
• Enables higher pigment
concentration in the spraying
liquid and thus comparable
process times to achieve a
comparable opacity

PVA film coating with Parteck® TA and Parteck® COAT
Example formulation for best results
24
Coating Formulation Function Art. no.
7.5 % Parteck® COAT Film coating agent, polymer 141517
5.0 % Triethylcitrate Plasticizer 817059
2.5 % Parteck® LUB MST Anti-tacking agent 100663
10.0 % Parteck® TA Colorant 124069
Coating parameters
(labscale)
Value
Pan load (kg) 1-2
Pan size (L) 2.5
Inlet air flow (m3
/h) 45
Gun to bed distance (mm) 10 - 15
Inlet air temperature (°C) 70 - 80
Outlet air temperature (°C) 35 - 45
Spraying rate (g/min) 5 - 10
Pan Speed (rpm) 10 - 20
Pattern air pressure (bar) 0.3 – 0.7
Atomizing air pressure (bar) 0.1 – 0.3
Drying temperature (°C) 40 – 50
Disintegration time IPC
(n=6)
Hardness
IPC
Weight IPC
Raw cores: 500 mg
609 sec 296 N 541 mg
Galenical parameters of coated tablets:
IPC: In process control

Discover our toolbox for your coating formulations
25
Anti-tacking agents Article No.
Parteck®
LUB MST (MAGNESIUM STEARATE VEGETABLE GRADE)
EMPROVE®
ESSENTIAL Ph Eur, BP, JP, NF, FCC
100663
Parteck®
LUB CST (Calcium stearate vegetable grade) EMPROVE®
ESSENTIAL Ph Eur, BP, JP, NF, FCC
100664
Silicon dioxide colloidal, highly dispersed EMPROVE®
ESSENTIAL
Ph Eur, NF, JP, E 551
113126
Parteck®
LUB STA 50 (Stearic acid 50 vegetable grade) EMPROVE®
ESSENTIAL Ph Eur, BP, JP, NF
100661
Silicon dioxide colloidal, highly dispersed EMPROVE®
ESSENTIAL
Ph Eur, NF, JP, E 551
113126
Emulsifiers Article No.
Sodium dodecyl sulfate EMPROVE®
ESSENTIAL Ph Eur 817034
Tween®
20 (Polysorbate) EMPROVE®
ESSENTIAL Ph Eur, JP, NF 817072
Tween®
Tween®
Poloxamer 188 EMPROVE® EXPERT (stabilized with 70ppm BHT) Ph
Eur,NF
137112
Pigments Article No.
Titanium(IV) oxide EMPROVE®
ESSENTIAL Ph Eur, BP, USP, JP,
E 171
100805
Parteck®
TA (Calcium carbonate) EMPROVE®
ESSENTIAL
Ph Eur, BP, USP, E 170, FCC
124069
Plasticizers Article No.
Polyethylene glycol 200 EMPROVE®
ESSENTIAL DAB 8 817001
Triethyl citrate EMPROVE®
ESSENTIAL Ph Eur, JPE, NF, ChP 817059
Triacetin EMPROVE®
ESSENTIAL Ph Eur, BP, USP 103000
Parteck®
M 100 (Mannitol) EMPROVE®
ESSENTIAL
Ph Eur, BP, JP, USP, E 421
100494
Parteck®
SI 150 (Sorbitol) EMPROVE®
ESSENTIAL
Ph Eur, BP, JP, NF, JSFA, E 420
103583
Glycerol 85% suitable for use as excipient EMPROVE®
exp Ph Eur, BP
104091
Coating agent Article No.
Parteck®
COAT (Polyvinyl alcohol)
EMPROVE®
ESSENTIAL Ph Eur,ChP,JPE,USP
141517
Experience our products at
www.sigmaaldrich.com

26
• Your choice for an appealing white
finishing without TiO2
• Enhanced opacity in combination
with Parteck® COAT
Parteck® TA excipient:
DISCOVER
Looking for support to
re-formulate your products?
Contact our technical experts and learn more
about our outstanding application services:
applicationaction-technical@sigmaaldrich.com

The vibrant M, SAFC, Parteck, Emprove, Tween are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates.
All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2023 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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