Alternatives to titanium dioxide in tablet coating

Pharmaceutical Development and Technology

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Alternatives to titanium dioxide in tablet coating

Juliana Radtke, Raphael Wiedey & Peter Kleinebudde

To cite this article: Juliana Radtke, Raphael Wiedey & Peter Kleinebudde (2021) Alternatives to
titanium dioxide in tablet coating, Pharmaceutical Development and Technology, 26:9, 989-999,
DOI: 10.1080/10837450.2021.1968900
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
2021, VOL. 26, NO. 9, 989–999
/>
RESEARCH ARTICLE

Alternatives to titanium dioxide in tablet coating

Juliana Radtke, Raphael Wiedey and Peter Kleinebudde

Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitaetsstrasse 1, Duesseldorf, Germany

ABSTRACT ARTICLE HISTORY
Received 29 April 2021
Titanium dioxide (TiO2) is one of the most commonly used pharmaceutical excipients. It is widely used as Revised 5 August 2021
a white pigment in tablet and pellet coatings. However, it has recently been under massive criticism as a Accepted 12 August 2021
number of studies suggest a cancerogenic potential. It can therefore no longer be taken for granted that
TiO2 will continue to be universally available for drug products. Finding suitable alternatives is hence of KEYWORDS
special relevance. In this study, a number of different pigments were coated on tablets and their covering Titanium dioxide; tablet
potential analyzed. None of the alternative pigments showed comparable effectiveness and efficiency to coating; white pigments;
TiO2, though the CaCO3/CaHPO4-based coating showed the second-best results. Regarding the ability to Raman spectroscopy
protect photosensitive active ingredients, ZnO showed a comparable potential as TiO2, while all other
pigments failed. Using the alternative pigments as markers for in-line Raman spectroscopy as a process
analytical technology was challenging and led to increased prediction errors. Again, the CaCO3/CaHPO4-
based coating was the only of the tested alternatives with satisfying results, while all other pigments led
to unacceptably high prediction errors.

Introduction high public awareness. Intake of TiO2 can in principle take place
orally, dermally or by inhalation. The inhalation of very fine par-
Titanium dioxide (TiO2) occurs in four different modifications in ticles, especially nanoparticles, is generally regarded as critical
nature: anatase, rutile, brookite, and riesite, of which only anatase (Bakand et al. 2012). Animal studies have shown that nanopar-
and rutile are frequently used in pharmaceutical products ticles penetrate deep into the lungs and can lead to chronic
(Balachandran and Eror 1982; Tschauner et al. 2020). As a widely inflammation (Ernst et al. 2002; Muhle et al. 1989; Baggs et al.
used white pigment in pharmaceutical coating formulations, it ful- 1997). It was also observed that the inhalation of extremely high
fills various functions. On the one hand, it serves as a cosmetic TiO2 concentrations over a very long period of time led to an
whitener and enhances the intensity of colored coatings. On the increased formation of lung tumors in rats (Pott and Roller 2005;
other hand, the presence of TiO2 in the coating layer provides Heinrich et al. 1995). For example, rats were exposed to an aero-
protection for photo-sensitive active pharmaceutical ingredients sol containing 5 mg TiO2 per m3 for 24 months, 5 d a week, 6 h a
(APIs) in the tablet core. In the food industry, TiO2 is used under day (Muhle et al.1989). These and other studies form the basis for
the label E171 as a food additive, e.g. as a visual embellishment an ongoing European classification procedure for TiO2 according
in icings, chewing gums and also coated tablets (Titanium to the ‘Regulation on Classification, Labelling and Packaging (CLP)

Dioxide Manufacturers Association n.d.). The white pigment is also of chemicals with particularly hazardous substance properties’ (EC
contained in cosmetic products under the designation CI 7789 No. 1272/2008). In the course of this, TiO2 was classified by the
and as a UV filter/absorber in sunscreens (Titanium Dioxide Risk Assessment Committee of the European Chemicals Agency
Manufacturers Association n.d.). (ECHA) as ‘carcinogenic by inhalation’ in June 2017.

TiO2 shows the highest covering potential of all white pig- The probable reason for this cancerogenic effect is that par-
ments and has in addition a very high brightening capacity ticles can induce a chronic inflammation in the lungs (Bakand et
(Titanium Dioxide Manufacturers Association n.d.). This is reasoned al. 2012). This immune reaction most likely leads to an increased
in its high refractive index and its birefringent character. TiO2 in inflammation-based cancer risk. In the Annex published by ECHA,
the anatase modification has an average refractive index of 2.561 this new classification of TiO2 is justified by the occurrence of
and in the rutile modification of 2.900 (at k ¼ 589 nm (Haynes increased inflammation in rats that have inhaled large amounts of
2014)). TiO2 also shows a high Raman activity. Its frequent pres- TiO2 (Pott and Roller 2005). A study also showed an increase in
ence in pharmaceutical coating formulations simplifies the inline squamous cell carcinomas and bronchiolalveolar adenomas (Lee
process control of these coatings by Raman spectroscopy. Here, et al. 1985).
the applied coating mass during the process can be monitored
using the growing intensity of the characteristic TiO2 peaks With regard to oral intake however, the Risk Assessment
(Mu€ller et al. 2012). The anatase modification shows characteristic Committee concluded that there was no evidence of a carcino-
Raman peaks at wavenumbers of 640, 515, and 398 cmÀ1, the genic effect of TiO2 after oral intake (Annex 1 2017). Also, the
rutile modification at 612 and 448 cmÀ1. European Food Safety Authority (EFSA) concluded in 2016 that
there were no indications of health risks for consumers based on
TiO2 showed a cancerogenic effect in several studies and con- data available to date (European Food Safety Authority [EFSA]
sequently its wide use is an increasingly subject of criticism with

CONTACT Peter Kleinebudde Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitaetsstrasse 1, 40225
Duesseldorf, Germany

ß 2021 Informa UK Limited, trading as Taylor & Francis Group

990 J. RADTKE ET AL.

2016). The low absorption and bioavailability of TiO2 (< 0.1% of regarding three important functions of TiO2 in drug products: cre-
orally ingested amount) are emphasized. This factum is however ating a clear white surface with a high covering potential, protect-
not unanimous, since data suggesting a partial oral absorption of ing photo-sensitive APIs from light and serving as a marker for in-
TiO2 are known in the literature for a long time (Bo€ckmann et al. line Raman-spectroscopy as a PAT-tool during coating.
2000). After the publication of four new studies stating a potential
toxicity after oral intake (Bettini et al. 2017; Proquin et al. 2017; Materials and methods
Guo et al. 2017; Heringa et al. 2016) the EU Commission called for
a reassessment of this conclusion in 2018. Materials

Above all, the study by Bettini et al. from 2017 should be men- Tablet cores
tioned here (Bettini et al. 2017). TiO2 was administered to rats via The biconvex placebo cores consisted of 50% lactose (TablettoseVR
a gavage probe over seven days or over 100 days via drinking 80, Molkerei MEGGLE Wasserburg GmbH & Co. KG, Wasserburg
water. The used TiO2 was a product marketed as E 171 with am Inn, Germany), 49.5% microcrystalline cellulose (MCC, AvicelVR
44.7% of the particles being smaller than 100 nm (mass fraction). PH-102, FMC Corporation, Philadelphia, PA) and 0.5% magnesium
Among the observations made in the rats were effects on the stearate (Peter Greven GmbH & Co. KG, Bad Mu€nstereifel,
immune system, changes in the intestinal mucosa, and increased Germany). The nifedipine cores consisted of 5% nifedipine (Bayer
inflammatory parameters. A possible tumor-promoting effect was AG, Wuppertal, Germany), 35% MCC (SanaqVR 102, Pharmatrans-
derived from this (Bettini et al. 2017). EFSA concluded, even after Sanaq AG, Allschwil, Switzerland), 59% lactose (FlowLacVR 100,
a re-evaluation, that the 2016 assessment should not be revised. Molkerei MEGGLE Wasserburg GmbH & Co. KG, Germany) and 1%
However, data gaps regarding possible effects on the reproduct- magnesium stearate (ParteckVR LUB MST, Merck KGaA, Germany).
ive system are stated and further studies are recommended. In The properties of the tablet cores are given in Table 1.
addition, EFSA has set up a working group to further define the
specifications of food additives, e.g. with regard to particle size Coating suspensions
distribution.
For the investigation of the opacity of different coating suspen-
Despite the above assessments, in April 2019 the French gov-
ernment issued a regulation banning the placing on the French sions, colored tablet cores were needed. Therefore, four batches
market of food containing the food additive E 171 for a period of
one year starting 1 January 2020 (Le ministre d’Etat, ministre de of placebo cores were coated with a HPMC-based red immediate
la transition ecologique et solidaire, et le ministre de l’economie release coating suspension (AquapolishVR P red, Biogrund GmbH,

et des finances 2019). The decision is based on an expert opinion
of the French Agency for Food Safety, Environment and Health at Hu€nstetten, Germany). These red tablet cores were coated with
Work (ANSES). On 21 December 2020, the ban was expanded for
another year (Le ministre d’Etat, ministre de la transition four different white coating suspensions. The first suspension con-
ecologique et solidaire, et le ministre de l’economie et des finan-
ces 2020). tained 15% polyvinyl alcohol/polyethylene glycol graft copolymer
(KollicoatVR IR BASF, Ludwigshafen, Germany), 3% titanium dioxide
This expert opinion underlines the lack of scientific data which
is not compatible with the classification of TiO2 as safe for health (TiO2; KRONOS Worldwide, Inc., Dallas, TX) in the anatase modifi-
(Additif alimentaire E 171 2019). It calls for the collection of fur-
ther data to characterize the different physico-chemical forms of cation, 0.5% sodium lauryl sulfate (SDS) and 81.5% demineralized
TiO2 and additional toxicological data on the possible effects of
their uptake. In June 2019, EFSA responded with a statement con- water. The second suspension contained 15% polyvinyl alcohol/
cluding that the ANSES opinion does not contain significant new polyethylene glycol graft copolymer (KollicoatVR IR, BASF,
evidence that would justify a reassessment of TiO2 (EFSA 2019).
As early as 2017, the European Commission published a ‘Call for Germany), 3% zinc oxide (ZnO; Grillo Zinkoxid GmbH), 0.5% SDS,
Data’ calling for the ESFA recommended studies on reproductive
toxicity to be carried out and for more accurate characterization and 81.5% demineralized water. For the preparation of these sus-
by August 2019. A final EFSA assessment was expected by the
end of 2020, but has not been published to date. pensions, SDS and the pigment were added to water and dis-

Due to the extent of the debate and first precaution measures VR VR
by authorities, it can no longer be taken for granted that TiO2 will persed with an Ultra-Turrax (IKA -Werke GmbH & CO. KG,
continue to be universally available for drug products. Finding
suitable alternatives is hence of special relevance. Staufen, Germany) to achieve a homogenous suspension.
KollicoatVR IR was dissolved separately in water and then added to
Despite this relevance, only little work on this question has
been published so far. A study by the paint manufacturer Akzo the pigment suspension. In addition, two HPMC-based ready to
Nobel studied Zinc sulfide, zirconium dioxide, calcium carbonate
(CaCO3), and barium sulfate as alternatives to TiO2 in paint (de use coating mixtures were used. Both were applied as a mixture

Jong and Flapper 2017). The study concluded that none of the
studied pigments could achieve the opacity of a TiO2-containing of 15% coating suspension and 85% demineralized water.
formulation. For pharmaceutical applications, no study has been AquaPolishVR P white 014.117 (APP117, Biogrund GmbH,
published so far to the best of the author’s knowledge.
Hu€nstetten, Germany) is composed of hydroxymethylcellulose,
The aim of this study was therefore to test alternative white
pigments, with a special focus on recently introduced ready-to- hydroxypropylcellulose, polyethylenglycol, calcium carbonate
use mixtures that are specifically advertised as TiO2-free white
pigments. The suitability of the pigments should be investigated Table 1. Tablet core properties, n ¼ 20, x ± relative standard deviation.

Cores Diameter/mm Height/mm Band Mass/g
(%) (%) height/mm (%) (%)

Placebo 8.04 ± 0.31 3.80 ± 0.90 2.00 ± 0.37 200.9 ± 2.16
Nifedipine 12.61 ± 0.12 6.06 ± 0.20 2.44 ± 0.39 687.1 ± 1.50

Table 2. Investigated pigments with refractive indices.

Coating Pigment Refraction index

TiO2 TiO2 2.49
ZnO ZnO 2.0
APP117 CaCO3 1.66
Dibasic calcium phosphate 1.55
APP123 Magnesium carbonate 1.54
Microcrystalline cellulose 1.46
Dibasic calcium phosphate 1.55

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 991

VR the cores were coated with a mass gain of 7%. Samples of 100
tablets were taken during the coating process at mass gains of 1,
(CaCO3) and dicalcium phosphate. AquaPolish P white 014.123 2, 3, 4, 5, 5.5, 6, and 6.5%. The placebo cores for the Raman inves-
contains hydroxymethylcellulose, hydroxypropylcellulose, glycerin, tigation were coated with a mass gain of 3% for the TiO2- and
magnesium carbonate, MCC, and dicalcium phosphate. Table 2 ZnO-containing coatings and 5% for APP117 and APP123. For
indicates the pigments which were included in the investigation each coating suspension, a calibration and a test batch was
and their refractive index. coated. To also study the effect of coatings on drug stability, 15
nifedipine tablet cores were added to the coating process. They
For the opacity study, the four coating suspensions were were of larger size (12 mm) than the other tablets and could
applied to the red cores. To investigate the suitability of Raman therefore be manually selected from the batches after coating.
spectroscopy, the four coating suspensions were applied to pla-
cebo cores. The coating parameters for this study are given in Table 4. All
cores were coated with an inlet air volume of 100 m3/h. The tab-
Methods let batch size was 3800 g for all coating runs.

Particle size distribution Scanning of coated tablets
The particle size distribution of the pigments was determined by To determine the opacity of various white coatings, the tablets
laser diffraction (Mastersizer 3000, Malvern Instruments, Malvern, were scanned at different sample times and at the end of the
UK). For this purpose, all samples were dispersed in water and process using a standard computer scanner (Epson Perfection
measured three times using the wet-dispersion unit. The concen- V800 Photo, Suwa, Japan) . The images were taken at a resolution
tration of sample in water was selected in such a way that an of 300 dpi with a color depth of 48 bits. No color correction was
optimal laser obscuration of 2 À 6% was guaranteed. Any agglom- applied. Per sample time 40–50 tablets were measured, in add-
erates of particles were deagglomerated by ultrasound prior to ition six white tablets were measured as reference. The tablets
each measurement. Using the corresponding software, the particle were arranged in rows of 5. The edges of the scan support were
size distribution was determined from the data based on the Mie covered with white paper. Since the scanner could not be closed
theory and given as volume distributions. The refractive index during the measurement, all measurements were carried out
was adjusted depending on the material. For ZnO a refractive under exclusion of light. Each scan was performed three times, an
index of 2.0034 and for TiO2 of 2.493 was applied (Bodurov et al. average image of the three images created and used
2016). Since the ready-to-use mixtures (APP117 and APP123) con- for evaluation.
tained i.a. dibasic calcium phosphate, the refractive index of dical-

cium phosphate (1.55) was applied for the respective Image analysis for opacity determination
measurements. The x10 quantile and the x50 quantile from the The image analysis was performed in Python version 3.7 (Python
obtained distribution curves were used to describe the particle Software Foundation, Wilmington, DE). The OpenCV library was
size. Determination was challenging for the ready-to-use mixture, used. The RGB color values obtained were converted into the cor-
since they contained further excipients like polymers and stabil- responding HSV and Lab color values. In the HSV color space, H
izers. All other excipients except the pigments were however sol- (hue) describes the hue, S (saturation) the color saturation, and V
uble and therefore expected not to interfere with the particle size (value) the light value. The V-value can take values between 0 for
determination. This was especially the case, since the sample was black and 1 for white. The H and S values from the HSV color
strongly diluted with water before measurement. space were included in the evaluations of this work. The Lab color
space describes all perceptible colors in a three-dimensional color
Coating of tablets space. The brightness value L (luminance) is perpendicular to the
All coating processes were performed in a laboratory drum coater color planes a and b. The coordinate indicates the color type and
with a drum size of 5 l (BFC 5, L.B. Bohle Maschinen ỵ Verfahren intensity between green and red, the b coordinate between blue
GmbH, Ennigerloh, Germany). Two 1.0 mm nozzles (Du€sen-Schlick and yellow. The luminance can take values between 0 and 100,
GmbH, Untersiemau, Germany) were installed for the application where L ¼ 0 stands for black and L ¼ 100 for white. From the Lab
of the coating suspensions. The distance between the nozzles and color space, only the L values were used directly for evaluation to
the tablet bed was 10 cm. Process parameters for the application track changes in brightness during coating. In addition, the color
of the different coating suspensions for the opacity study are
given in Table 3. To study the opacity of the different coatings,

Table 3. Coating process parameters, opacity trial.

Coating Inlet air temperature/C Outlet air temperature/C Pan speed/rpm Spray rate/g/min Sprayed coating mass/g

APP red 60 40 16 11–12 876
41 16 11–12 1510
TiO2 61 41 16 11–12 1510
41 16 11–12 1862
ZnO 61 41 16 11–12 1862

APP117 62

APP123 62

Table 4. Coating process parameters, Raman trial.

Coating Inlet air temperature/C Outlet air temperature/C Pan speed/rpm Spray rate/g/min Sprayed coating mass/g

TiO2 58 40 15 7–8 647
40 15 7–8 647
ZnO 58 41 16 11–12 1330
41 16 11–12 1330
APP117 58

APP123 58

992 J. RADTKE ET AL.

distance, Delta E, was calculated in this color space. Here, the Crushing strength and tablet geometry
color distance to white was calculated and evaluated. According Crushing strength, diameter, height, and mass of the tablets were
to EN ISO 11664-4 (International Organization for Standardization determined using the Smart Test50 tablet tester (Dr. Schleuniger
2008) Delta E between two colors is calculated as Euclidean dis- Pharmatron, Thun, Switzerland). For each core type, 20 tablets
tance using Equation (1): were measured. The breaking force was standardized according
to Fell and Newton by calculating the tensile strength (Fell and
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Newton 1970). The cap height was measured for 20 tablets with a
DE1, 2 ẳ L1L2ị2 ỵ a1a2ị2 ỵ b1b2ị2 (1) calliper (Digital ABS Caliper, Mitutoyo Corporation,
Kawasaki, Japan).
The image analysis was performed for a circular area in the
center of each tablet. The area of the analyzed region was half of Photostability study
the tablet cap. The OpenCV-based evaluation leads to the HSV

and Lab values for each tablet recorded. These were then statistic- Storing conditions
ally evaluated by calculating the mean value, standard deviation The embedded nifedipine tablet cores were protected from light
and confidence interval (95%). The accuracy of the measurements exposure by a TiO2-containing coating or one of the three alterna-
was checked using the values of the white reference tablets. tive TiO2-free white coatings (ZnO-containing, APP117, or
APP123). Nifedipine is an aromatic compound of the dihydropyri-
Coating thickness determination dine-type and, like other members of this group, shows a pro-
The coating thickness of the three coatings at a mass gain of 7% nounced sensitivity to light (Ebel et al. 1978). As shown in Figure
was calculated using the volume and the density of the applied 1, nifedipine degrades to a nitrophenylpyridine analog (impurity
coating. For density measuring, coated films were produced for A) and a nitrosophenylpyridine analog (impurity B) under the
all coating formulations. Films were casted using a Coatmaster influence of light.
510 (Erichsen, Hemer, Germany). The plate was heated to 40 C to
simulate the conditions during the coating process. The suspen- According to Lehto et al., nifedipine shows maximum instabil-
sions were casted using a coating knife with a gap width of ity in the solid-state at a wavelength of 455 nm (Lehto et al.
800 mm. The film forming was completed after a drying time of 1999). The protective capacity of the four coatings was investi-
30 min. The density of the casted film was measured by gas pycn- gated on the basis of a stability test in a light chamber at a wave-
ometry (AccuPyc 1330, Micrometics Instrument Corp., Norcross, length between 315 and 400 nm, which is not the worst-case
GA). For all measurements, the temperature was kept constant at wavelength, but still was considered to be high relevance. The
25 C. The volume of the coating was calculated from the total light chamber was equipped with four fluorescent tubes with a
tablet surface of the tablets and the applied coating mass. The UVA radiation power of 3.5 W (SUPRATEC 18 W/73, OSRAM GmbH,
change of the tablet surface during the coating process was Mu€nchen, Germany). In each case, six tablets per coating were
assumed to be negligible. The coating efficiency was determined stored in the light cabinet and exposed to UV light for 2 or
by weight analysis after each coating process and included in the 4 weeks. The tablets were flipped over every week to ensure a
calculations. uniform light irradiation from both sides of the tablets. Three tab-
lets each were removed after 2 weeks and 3 after 4 weeks and
the content determined by HPLC. In addition, the content of

Figure 1. Molecular structure of nifedipine and its degradation products: a) impurity A; b) impurity B.

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 993

uncoated nifedipine tablets was determined after 2 and 4 weeks Partial least squares regression (PLSR)
of storage in the light cabinet and after 4 weeks of storage in Partial least squares regression (PLSR) was performed using
the dark. MatlabVR R 2018b. The models were built by regression of the
inline-measured Raman spectra (X-data) against the applied mass
HPLC analysis of coating suspension (Y-data). As the signal of the Raman active
The coated and non-coated nifedipine tablets were weighed after ingredients increases linearly with the mass of applied coating
removal from the light cabinet and each was dissolved in 20 ml suspension, a linear increase of the Raman spectra during the
methanol and diluted with the mobile phase to 50.0 ml. The coating process was assumed. Data of the entire coating run were
mobile phase consisted of nine parts acetonitrile, 36 parts metha- included in the PLSR model. The spectral range and optimal num-
nol, and 55 parts distilled water. To ensure a complete dissolution ber of factors were defined individually for each coating formula-
of the API, the samples were treated in an ultrasonic bath for tion in dependence of the model prediction performance ability.
20 min and shaken regularly. The samples were handled under Models were built with the data of the calibration data set and
exclusion of light and the dissolved sample was transferred into tested with the new data of a test data set.
light-protected amber glass vials. Three tablets per coating prep-
aration were examined, whereby the content was determined Results and discussion
three times by HPLC. The analysis was carried out according to
Ph. Eur. 2.2.29 (European Pharmacopoeia 9.0 2017), which Covering capacity
describes the test for related substances of nifedipine. The HPLC
(VWR Hitachi HPLC, VWR International GmbH, Darmstadt, Visual inspection
In dependence of the coating formulation, a mass gain of 7% cor-
VR responded to a different layer thickness. The TiO2-containing coat-
ing showed a maximum layer thickness of about 90 mm, the ZnO-
Germany) was equipped with a LiChrospher RP-18 5 mm column containing coating of 86 mm, APP117 of 77 mm, and APP 123 of
(Merck KGaA, Gernsheim, Germany). Nifedipine was identified by 86 mm. The TiO2 and ZnO-containing coating layers both had a
the retention time given by the Pharm. Eur. and by comparison pigment content of 20%. Since APP117 and APP123 are ready-to-
with chromatograms of pure nifedipine. The impurities were iden- use mixtures, the pigment content is unknown here. Figure 2
tified by relative retention times from literature: 0.72 for the nitro- shows tablets, which were coated with the different coatings with
phenylpyridine analog and 0.86 for the nitrosophenylpyridine a mass gain between 1 and 7%. By the visual inspection, it
analog (Florey 1990). In absence of pure degradation products for becomes clear that the coatings showed different cover-
reference, impurities A and B were quantified by comparing the ing capacities.

peak areas of the nifedipine peaks and the peak areas of the deg-
radation products. The absolute values for concentration might Even at smaller mass gains, the TiO2-containing coatings
therefore by to a certain extent flawed, relative comparisons showed a high opacity. Thus, the tablets appear almost white
are valid. even with a mass gain of 3%, with the application of higher mass
gains only slight changes could be achieved. This also explains
Raman spectroscopy the fact that non-functional TiO2-containing coatings are usually
applied with a target mass gain between 3 and 4%. A comparable
Raman spectra were measured in-line using a Raman RXN2 ana- opacity is only achieved with APP117 at mass gains > 5%.
lyzer (Kaiser Optical Systems, Inc., Ann Arbor, MI) with a PhAT APP117 showed the second-highest opacity, despite the slightly
probe. As this non-contact optic device forms a spot with a diam- lower coating thickness. The optical differences between the ZnO-
eter of 6 mm, it allows the measurement of a larger sample area. containing coating and APP123 were hardly visible, whereby the
The diode laser operates at 785 nm with a laser power of 400 mW. opacity of the ZnO-containing coating appeared slightly higher.
The PhAT probe was installed through the front door of the Both coatings showed an insufficient opacity at mass gains < 7%
coater. During measurements, the optic of the PhAT probe was and were not able to completely cover the red color of the tablet
dedusted permanently with compressed air. The probe was cores. Even at mass gains of 7% the red color of the cores is
installed with a distance of 21 cm to the tablet bed. The iC still visible.
RamanTM software package (Kaiser Optical Systems, Ann Arbor, MI)
was used for data acquisition. During the coating processes one Image analysis
spectrum was collected every 10 s. The exposure time was set The results, which are shown in Figure 2, are only based on
between 2 and 3 s. optical considerations, these observations should be supple-
mented with quantifiable results using a computer scanner.
Data analysis methods
Figure 2. Red tablets with increasing mass of coated white pigment.
Data pretreatment
Before model building, the measured Raman spectra were pre-

VR

treated using Matlab R 2018b (The MathWorks, Inc., Portola
Valley, CA). A moving average with a window size of 12 was

applied to the raw spectra. Then, spectra were preprocessed using
standard normal variate (SNV). The preprocessed range of wave-
numbers depended on the applied coating layer and was chosen
accordingly with regard to the model performance parameters.
For each coating process, models were built and tested with dif-
ferent spectral ranges to find the range, which led to the smallest
root mean square error of prediction (RMSEP).

994 J. RADTKE ET AL.

Figure 3. Change of color measures with increased coating mass.

Images of samples, which were taken during the coating proc- ‘v’ describes the brightness in the HSV color space, it is expected
esses and at the end of the process, were obtained using this to increase while coating colored cores with white coating formu-
scanner. For each sample time point, approximately 50 tablets lations. Such an increase was observed during the application of
were scanned and examined by image analysis. The values of the all four coating formulations (Figure 3). However, the TiO2 con-
Lab- and HSV-color space were determined using the obtained taining coating again showed a clear superiority with a brightness
images and calculations were based on a circular area in the mid- value of 0.87 at the end of the process. Among the TiO2-free coat-
dle of the tablet cap. The v-, S-, and L-values were considered for ings, APP117 showed the highest brightness value (0.79). With the
evaluation. In addition, the color distance to white (Delta E) was ZnO-containing coating and APP123 a maximum brightness of
calculated. Figure 3 shows the results, which were obtained by 0.72 was achieved at the end of the process. These results are
image analysis. consistent with the visual observations, which were described in
3.1.1. The TiO2 containing coating appeared whitest, followed by
As the white coatings should cover the red tablet core, a the APP117. The two other coatings did not show a sufficient cov-
decrease of saturation was expected during the coating process ering ability even for higher mass gains. ‘L’ indicates the lumines-
and with an increasing weight gain. The saturation decreased by cence and describes the whiteness in the Lab color space. As
the application of all four coating formulations (Figure 3). At a expected, the progression of L was very similar to the progression
mass gain of 1% the TiO2-containing coating could reduce the of v. So, the observations, which were based on v, can be trans-
saturation under 0.1. In comparison, a value of 0.23 was achieved ferred to L. Also, considering Delta E, the TiO2-containing coating
using APP117, 0.27 using APP12, and 0.31 with the ZnO-contain- was the most efficient and effective coating in terms of covering

ing coating. The initial saturation of the uncoated tablet cores capacity. Delta E was calculated as the color distance to pure
was 0.48. At a mass gain of 3%, tablets, which were coated with white with an L-value of 100. At a mass gain of 7%, the tablets,
the TiO2-containing coating, showed a saturation of 0.035 and which were coated using the TiO2-containing coating, showed a
even the application of higher mass gains resulted only a slight Delta E value of 13.4. This was the lowest achieved Delta E value,
decrease in saturation. With a final mass gain of 7% a saturation however, a visual difference to white could still be recognized in
of 0.031 was achieved. These results confirmed the visual observa- front of a white background.
tions, in which the TiO2-containing coating showed a high cover-
ing ability even at lower mass gains. Also, the application of The results are in good alignment with results from Rowe, who
APP117 reduced the saturation to 0.03 at a mass gain of 7%. studied the opacity of various pigments using a colorimeter (Rowe
However, a higher mass gain of 5% was necessary to achieve 1984). The white pigments CaCO3, calcium sulfate, talc, and TiO2, as
comparable results as the TiO2-containing coating. The ZnO-con- well as a number of non-white pigments were comprised in the
taining coating and APP123 led to a lower decrease in saturation, coating layers and compared regarding opacity. The opacity was
at a mass gain of 7% both showed a saturation about 0.06. With determined as the contrast ratio of measurements in front of a
the TiO2-containing coating this value was already achieved with black and a white background. Without the addition of a pigment,
a mass gain of 2% and with APP117 with a mass gain of 4%. As the contrast ratio was 33.3%, with TiO2 as a pigment 91.6%, with

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 995

Figure 4. 50% and 10% quantiles of the particle size distributions determined by laser diffraction.

CaCO3 46.7%, and with talc 46.4%. Also in the study of Rowe, TiO2 cellulose (Sultanova et al. 2013), and by that only slightly below
shows a significantly higher opacity compared to the other pig- the values for APP117. The higher particle size can therefore be
ments which is in agreement with the results of this study regarded as one of the reasons for the inferior opacity of APP123.
(Rowe 1984). The quantitative composition of APP123 and APP117 is not
known, so more precise conclusions are not possible.
Particle size of pigments
The opacity of white pigments is largely due to their ability to Due to the generally known dependence of opacity on particle
scatter incident light. In addition to the properties of the incident size, the data shown could only be partially explained. In addition
light, the scattering depends on the optical properties of the par- to particle size, other factors, such as refractive index, surface
ticle and its particle size, shape, surface texture, spatial orienta- properties, particle spacing, and special features, such as the band

tion, arrangement of the particles, etc. (Nelson and Deng 2008). gap of the ZnO described above must also be taken into account.
Up to a certain level the light scattering and thus the opacity of a It should also be noted that the pigment content in the coatings
particle can be increased by reducing the particle size. Below a investigated could not always be kept constant. Above all, the
certain particle size however, the efficiency of light scattering high opacity of TiO2 and the low opacity of APP123 can be
decreases again, for example TiO2 particles with sizes < 0.1 mm explained by the large differences in particle size.
show a decrease in light scattering and thus in the resulting opa-
city (Diebold 2014). Since the human eye shows the highest sensi- Effect on photostability
tivity to yellow-green light (wavelength around 0.55 mm), the
optimum diameter of commercial white pigments is on average Many APIs show a light sensitivity due to their photo reactivity
0.2–0.3 mm (Winkler 2013). The particle sizes of the pigments of (Albini and Fasani 1998). The European Pharmacopeia requires
the four white coatings used were determined by laser diffraction light protection for more than 250 APIs. This sensitivity to light
using wet dispersion in water. TiO2 showed the smallest particle poses a challenge both for formulation development and for the
size with a x50 value of 0.403 mm and a x10 value of about manufacturing process of pharmaceuticals. If it is a tablet, light
0.007 mm (Figure 4). protection can be ensured by an opaque coating. If such a coat-
ing is not applied, light protection is only guaranteed by the
Here, the x50 value was closest to a particle size of 0.2–0.3 mm packaging. Here, no permanent light protection can be guaran-
described as optimal. The high opacity of the TiO2-containing teed, especially during the handling of the dosage form by the
coating can therefore be explained not only by the high refractive patient. The light protection provided by the four different coat-
index and the birefringence character of TiO2, but also by the ings used in this article was investigated using the model
small particle size. All other pigments used had significantly drug nifedipine.
higher particle sizes. ZnO and APP117 showed comparable x10
and x50 values, whereas pure ZnO with a x50 value of 3.5 mm and The nifedipine tablets were coated with a mass gain of 7%.
a x10 value of 1.2 mm showed slightly smaller particles than The coated tablets were then stored under UV light (315–400 nm).
APP117 (x50: 4.1 mm, x10: 1.9 mm). Despite the small particle size The content of degradation products was determined after 2 and
and a rather high refractive index of 2.0 (Haynes 2014), the ZnO- 4 weeks (Figure 5).
containing coating showed insufficient opacity, as seen in Figure
3. This can be explained by the wide energy band gap of ZnO at While the European Pharmacopoeia requires that concentra-
Eg%3.3 eV (Srikant and Clarke 1998). It causes an increased light tions of degradation products are limited to 0.1% of the nifedi-
transmission at wavelengths in the visible range (above 400 nm) pine content, reference tablets without any coating showed
(Struk et al. 2010). Since opacity is the reciprocal of transmission, concentrations of 0.16% (impurity A) and 3.33% (impurity B) after

this results in a reduction of opacity. APP117 showed a signifi- 2 weeks (Figure 5). After 4 weeks the levels increased to 0.24 and
cantly higher opacity compared to APP123. This corresponds to 4.02%. Tablets stored in the dark showed concentrations of 0.01
the result of the particle size measurement. With a x50 value of and 0.00% after 4 weeks.
16.3 mm and a x10 value of 6.2 mm, APP123 had by far the largest
particles. APP117 contains CaCO3 with a refractive index of 1.66 Regarding impurity A, ZnO-containing showed the lowest con-
(Haynes 2014) and dibasic calcium phosphate with a refractive centrations after 2 as well as after 4 weeks. For both points in
index of 1.55 (Haynes 2014) as insoluble components. The refract- time, the concentrations were below 0.1% and the requirements
ive indices of the insoluble components of APP123 are 1.54 for of the European Pharmacopeia therefore fulfilled. TiO2 showed
magnesium carbonate (Haynes 2014) and 1.46 for microcrystalline similar results as ZnO for impurity B and slightly higher concentra-
tions with higher variability for impurity A.

The tablets coated with APP117 and APP123 exceeded the
specified limits both after 2 and after 4 weeks. Compared to the

996 J. RADTKE ET AL.

Figure 5. Concentration of degradation products after 2 and 4 weeks storage under UV light.

other two coatings, more nifedipine was converted to impurity A, Table 5. PLSR-model building and prediction parameters.
whereby the content of the tablets coated with APP117 after
2 weeks was at comparable levels as the un-coated refer- Coating Range/cmÀ1 Components R2 RMSEC/% RMSEP/%
ence tablets.
TiO2 340–800 3 0.9998 0.37 0.97
The conversion of nifedipine into impurity B in both the TiO2- ZnO 700–1600 6.97
and the ZnO-containing coating was completely prevented during APP117 800–1550 3 0.9982 1.22 2.06
the first 2 weeks, as the concentrations were below the limit of APP123 900–1500 3.82
detection. After 4 weeks under light irradiation, however, values 3 0.9986 1.09
close to or just above 0.1% were also achieved here. This does
exceed Pharmacopeia limitation, but it should be considered that 2 0.9935 2.34
extreme conditions were chosen here. Furthermore, comparison

to the other coatings clearly shows significant differences. APP117 sampling point. Even with TiO2 concentrations up to 29.5%, a film
and APP123 could not sufficiently protect the active substance thickness between 24 and 68 mm was not sufficient to protect
against photo-induced conversion. Here, more than 2% of the nifedipine from light degradation. The film thickness was deter-
nifedipine was converted to impurity B, so that the conversion to mined as a key variable for the light protection of nifedipine.
it could only be slightly reduced compared to the tablets that Good light protection was provided with a film thickness of
were not coated. There was no difference in the determined con- 145 mm. In this study, a good light protection of nifedipine was
tents of impurity B after 2 and after 4 weeks. achieved with lower TiO2 concentrations (16.2% w/w) and a lower
film thickness (90 mm).
The best light protection was achieved by the ZnO-containing
coating. In addition, this coating was the only one that could suf- Inline monitoring using Raman spectroscopy
ficiently prevent the conversion of nifedipine into impurity A. This
can be explained by the pronounced photoprotective property of To test the applicability of inline monitoring using Raman spec-
ZnO, which is particularly pronounced in the wavelength range of troscopy for the TiO2-free alternative coatings, PLSR models were
UVA radiation (320–400 nm) (Smijs and Pavel 2011). This wave- built using the data of the four calibration data sets. For each
length range corresponds to the wavelength range of coating formulation a prediction model was built which was used
315–400 nm used for the experiments shown. TiO2 also has a pho- to predict the applied coating mass of the corresponding test
toprotective character, which is mainly observed in the UVB radi- data set. Model building and prediction parameters are given in
ation range (290–320 nm) (Smijs and Pavel 2011). TiO2 and ZnO Table 5. A number of two or three components were used for
are often found in sunscreens. In that context a higher protection model building.
by ZnO compared to TiO2 in the UV range has already been
described in the literature (Pinnell et al. 2000). The PLSR model for the prediction of the TiO2-containing coat-
ing showed the smallest calibration error (0.37%) and the highest
The protection of light-sensitive APIs by a TiO2-containing R2 (0.9998). This model resulted in the smallest prediction error
coating was already investigated in a study by Bechard et al., under 1%. As shown in the observed vs. predicted plot, the
which examined the light protection by an HPMC-based coating applied coating mass was predicted very precisely (Figure 6). With
(TiO2 content: 29.5% w/w) with different mass gains (Bechard et values between 1.09 and 2.34% the PLSR models of the alterna-
al. 1992). The coated cores contained 12% (m/m) nifedipine. They tive coating formulations showed higher calibration errors. In add-
were coated with mass applications of 2, 4, 6, 10, and 15% and ition, the R2 values were smaller. Here, the APP117 prediction
then irradiated with white fluorescent light (12 Â 15 W) in a light model showed the most promising calibration parameters with a
cabinet. A clear coating without the addition of a pigment RMSEC of 1.09% and a R2 of 0.9986. This model was able to pre-

showed no light protection, there was no difference in the con- dict the application of APP117 with an acceptable RMSEP of
version of nifedipine compared to the uncoated cores. In their 2.06%. However, the predicted coating mass showed higher devi-
study, nifedipine showed an initially high decomposition rate in ations from the observed coating mass compared to the TiO2-con-
the first 2–3 d. This is in agreement with the results of this study, taining coating (Figure 6).
in which most of the degradation took place before the first
With an RMSEP of 6.97%, it was not possible to build a reliable
PLSR model for the ZnO-containing coating. As shown in Figure
6, the applied coating mass was overestimated during the entire

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 997

Figure 6. Coating mass predicted by PLSR plotted against observed coating mass.

coating process. Also, the application of APP123 could not be pre- containing coating. TiO2 was superior regarding efficiency as well
dicted with an acceptable prediction error. In the beginning and as effectiveness, i.e. the achieved opacity was the highest and
at the end of the process the applied coating mass was underesti- was reached using the minimal mass gain. The CaCO3 and
mated, which led to an RMSEP of 3.82%. The results can be CaHPO4-based coating were the second-best regarding both crite-
explained with regard to the spectral changes during the coating ria. Regarding the protection of a photosensitive API, ZnO seemed
process. As TiO2 is a strong Raman marker, the related peaks to be a suitable alternative to TiO2 while CaCO3-, MgO-, and
showed a distinctly and linear intensity increase during the coat- CaHPO4-based coatings could not protect a photosensitive API in
ing process. Also, the increasing intensity of the CaCO3 peaks dur- the coated tablet at increased light exposure, which led to
ing the application of APP117 enabled a model building with an increased degradation.
acceptable predictive ability. Compared to TiO2, CaCO3 showed a
lower Raman intensity which resulted in smaller changes in the In-line process control of the coating processes of all four coat-
Raman spectra during the process and explains the comparatively ings used by means of Raman spectroscopy showed that replac-
higher prediction error. During the application of the ZnO-con- ing TiO2 would be a major challenge. Acceptable prediction errors
taining coating and APP123 no sufficient spectral changes were could only be achieved for one of the TiO2-free alternatives
obtained to build a reliable PLSR model. (APP117). But also here the prediction errors were in a signifi-
cantly higher range compared to the TiO2-containing coating due
Conclusion to the reduced Raman activity of the pigment. Difference spectra

and the implementation of a moving average could increase the
The TiO2-free white coatings used in this study are inferior to the prediction capability of PLSR models. However, this was only the
TiO2-containing white coating in some of the investigated proper- case, if the applied coating showed sufficient changes in the
ties. Especially with regard to opacity and appearance, no alterna- Raman spectra over process time.
tive white coating could achieve a similar result as the TiO2-
In conclusion, the presented data demonstrate that some alter-
native pigments – especially the combination of CaCO3 and

998 J. RADTKE ET AL.

CaHPO4 – show promising results, but none possesses all desired Ebel S, Schu€tz H, Hornitschek A. 1978. Studies on the analysis of
attributes. Further work on this larger question is desired, taking nifedipine considering in particular transformation products
into account more potential pigments, ideally all in the desired formed by light exposition. Arzneimittelforschung. 28(12):
sub-micron size range. 2188–2193.

Acknowledgments European Food Safety Authority [EFSA]. 2019. EFSA statement on
the review of the risks related to the exposure to the food
The authors thank Rok Sibanc, who developed the software for additive titanium dioxide (E 171) performed by the French
color analysis of the coated tablets. Furthermore, the authors Agency for Food, Environmental and Occupational Health and
extend our appreciation to BASF and Biogrund for providing the Safety (ANSES). EFSA J. 17(6):5714.
excipients as well as L.B. Bohle for providing the tablet cores.
Ernst H, Rittinghausen S, Bartsch W, Creutzenberg O, Dasenbrock
Disclosure statement C, Go€rlitz BD, Hecht M, Kairies U, Muhle H, Mu€ller M, et al.
2002. Pulmonary inflammation in rats after intratracheal instilla-
No potential competing interest was reported by the authors. tion of quartz, amorphous SiO2, carbon black, and coal dust
and the influence of poly-2-vinylpyridine-N-oxide (PVNO). Exp
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