Journal Pre-proof

Molecular state evaluation of active pharmaceutical ingredients in adhesive patches

for transdermal drug delivery

Katsuhiko Gato, Mika Yoshimura Fujii, Hiroshi Hisada, James Carriere, Tatsuo Koide,
Toshiro Fukami

PII: S1773-2247(20)30864-9
DOI: https://doi.org/10.1016/j.jddst.2020.101800
Reference: JDDST 101800

To appear in: Journal of Drug Delivery Science and Technology

Received Date: 20 April 2020

Revised Date: 2 May 2020
Accepted Date: 7 May 2020

Please cite this article as: K. Gato, M.Y. Fujii, H. Hisada, J. Carriere, T. Koide, T. Fukami, Molecular
state evaluation of active pharmaceutical ingredients in adhesive patches for transdermal drug
delivery, Journal of Drug Delivery Science and Technology (2020), doi: https://doi.org/10.1016/
j.jddst.2020.101800.

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 CRediT author statement

Ref: JDDST_2020_821

Title: Molecular state evaluation of active pharmaceutical ingredients in adhesive

patches for transdermal drug delivery

Authors:

Katsuhiko Gato: Conceptualization, Methodology, Investigation Writing - Original

Draft

Mika Yoshimura Fujii: Methodology, Formal analysis, Writing - Review & Editing

Hiroshi Hisada: Resources, Visualization

James Carriere: Resources, Writing - Review & Editing

Tatsuo Koide: Validation, Writing - Review & Editing

Toshiro Fukami: Conceptualization, Writing - Review & Editing, Supervision

1
 Regular article

Molecular state evaluation of active pharmaceutical ingredients in

adhesive patches for transdermal drug delivery

Katsuhiko Gato a, Mika Yoshimura Fujii a, Hiroshi Hisada a, James Carriere b,

Tatsuo Koide c, Toshiro Fukami a*

a
Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Kiyose,

Tokyo 204-8588 Japan

b
Coherent Inc., 850 East, Duarte Road, Monrovia, California 91016, United States
ｃ
Division of Drugs, National Institute of Health Sciences, Tonomachi, Kawasaki-ku,

Kawasaki, 210-9501 Japan

*Corresponding author:

Toshiro Fukami PhD

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University

2-522-1 Noshio, Kiyose, Tokyo 204-8588 Japan

TEL & FAX: +81-42-495-8936

E-mail: [email protected]

1
Abstract

In this study, we prepared mock patches consisting of model drug (felbinac) and three

types of acrylic polymers with different functional substituent and/or physical properties,

and evaluated the correlation of pharmaceutical properties and molecular state of

felbinac in these patches. Polarized light microscopic observation, powder X-ray

diffraction and Raman spectroscopy were employed and then different propensity was

observed in the crystallization behavior and precipitated crystal form in each patches. In

particular, Raman spectra in low frequency region were useful to detect polymorphic

change in patches. 1H-NMR was also used to investigate the interaction between

felbinac and the polymers. In addition, pharmaceutical properties of mock patches were

evaluated by dissolution test and in vitro skin permeation test. From these results,

crystallization of felbinac was occurred in the case of weaker interaction between

felbinac and the polymer, which has carboxy group as substituent, and resulted in higher

drug release and skin permeation. In conclusion, it was essential to consider the

compatibility of drug and polymer, which constituted adhesive layer in patches, in

molecular level.

Keywords
low frequency Raman spectroscopy, patch for transdermal drug delivery system,

adhesive layer, crystal form, dissolution, in vitro skin permeability

2
1. Introduction

Felbinac (Fig. 1) is a derivative of phenylacetic acid and classified in non-steroidal

anti-inflammatory drug (NSAID) with analgesic actions. Felbinac has been used as

adhesive patches for transdermal drug delivery system [1] since 1990s and marketed as

various external preparations [2-3] such as lotions, creams, sticks and gels.

In general, the transdermal administration route has advantages such as ability to

bypass the liver first-pass effect and easy administration management [4]. In addition, it

can be expected to avoid gastric mucosal injury by inhibiting COX-1 in gastric mucosal

epithelial cells, which is a side effect of NSAIDs [5]. In particular, many NSAIDs have

been developed as patches which can maintain their pharmacological effect over long

periods and therefore improve patients' adherence.

In patches, the active pharmaceutical ingredient (API) is dispersed or dissolved in a

hydrophobic polymer constituting an adhesive layer, and the molecular state of API

would affect its skin permeability [6]. In addition, differences in crystalline

polymorphism are known to affect the percutaneous absorbability of the drug [7].

Therefore, it is essential to control the molecular state of API in the patch in order to

ensure its steady activity through the concept of quality by design (QBD).

To evaluate the molecular state of API in drug products, powder X-ray diffraction

(PXRD) analysis [8], nuclear magnetic resonance (NMR) [9], Fourier transform

Infrared spectroscopy (FT-IR) [10-11], near-Infrared spectroscopy (NIR) [12], Raman

spectroscopy [13-14] and other methods have been used. In particular, Raman

spectroscopy, which includes conventional and low-frequency (LF) types, is widely

used for that purpose, because its microscopic mode enables to visualize distribution of

pharmaceutical ingredients in dosage form as chemical imaging.

3
 Whereas conventional Raman spectroscopy is often used to identify the chemical

compounds based on scattering peaks derived from their functional groups, the LF type

can be specifically employed to obtain information on the crystal structure including

molecular arrangement and intermolecular interaction from the LF Raman spectra

reflecting lattice vibration in the crystals [15-17]. We have previously reported the

utility of LF Raman spectroscopy with respect to the identification of crystalline drugs

in some dosage forms, the identification of pharmaceutical excipient polymorphism,

and the monitoring of crystal forms during manufacturing process as a PAT tool [6,

18-21].

In this study, felbinac mock patches were prepared using three kinds of acrylic

polymers with different functional substituents. The molecular state of API in the

adhesive layer was evaluated by polarized microscopic observation, conventional and

LF-Raman spectroscopy and PXRD measurement. In addition, NMR spectroscopy was

also performed to investigate the intermolecular interaction between felbinac and the

polymers. Finally, we demonstrated dissolution (drug release) and in vitro skin

permeation tests to evaluate the pharmaceutical properties of mock patches and the

influence of polymers.

2. Materials & Methods

2.1 Materials

Felbinac was purchased from Tokyo Chemical Industry Co., Ltd. (Japan). Three

types of acrylic polymers were donated by Daido Chemical Corporation (Japan). The

AO polymer has carboxyl groups, and the AV1and AV2 polymer have five-membered

lactam structures (Fig. 1). The viscosities of the acrylic polymers were evaluated as a
4
30% ethyl acetate solution (Table 1). 3M ScotchpakTM 1022 Release Liner Misc Size

and 3M ScotchpakTM 9732 Spak 2.05 Mil Heat Sealable Polyester Liner were donated

by 3M Japan Limited (Japan) for preparing the release liner and support liner of the

mock patches. For powder X-ray diffraction measurement with mock patches, Kapton R

polyimide film manufactured by Toray DuPont Co., Ltd. was supplied by Rigaku

Corporation (Japan).

2.2 Preparation of mock patches

Felbinac was dissolved in ethyl acetate to prepare a 10 mg/mL ethyl acetate solution.

This was mixed with various acrylic polymers at two weight percent of felbinac. Ethyl

acetate was volatilized from the mixed solution to obtain an appropriate viscosity, and

was then spread with a film applicator MULTICATOR 441 (manufactured by

ERICHSEN) on a release liner at a thickness of 1.0 mm. After drying at room

temperature for 15 hours, it was further dried at 60°C for 4 hours, and ethyl acetate was

distilled away. This was covered with a support liner and used as a mock patch [22].

2.3 Measurement of acrylic polymer concentration

Because of the high viscosity of acrylic polymers, each polymer shown in Table 1

was dissolved in ethyl acetate and adjusted to a manageable viscosity. For preparation of

mock patches, the concentrations of acrylic polymers were determined by thermal

gravimetric analysis (Thermo plus EVO2 TG-DTA manufactured by Rigaku Corp.

(Japan)). About 10 mg of acrylic polymer was weighed in an aluminium pan, and an

empty aluminium pan was used as a reference. The temperature was raised to 120°C at a

heating rate of 10°C/min to determine the amount of weight loss (weight percentage),
5
which was used as the amount of volatilized ethyl acetate. The mass loss was subtracted

from 100 to obtain the concentration of the acrylic polymer (weight percentage).

2.4 Felbinac content in mock patches

The patches were punched out in a circle of 12 mm in diameter, placed in a screw

tube, and 25 mL of ethyl acetate: methanol (1: 1) was added. The screw tube was

shaken with 800 rotations per minute for 5 minutes, and the amount of model drug

dissolved in the solution was determined by ultraviolet absorbance (UV mini

manufactured by Shimadzu Corporation, Japan) at 254 nm.

2.5 Polarizing microscopic observation

When the mock patches were stored at room temperature for 1 day, 1 week, 2 weeks,

3 weeks, and 4 weeks, appearance changes were observed using a polarizing

microscope (ML 9300 manufactured by Meiji Techno Co., Ltd. Japan). Observations

were conducted at ×10 and ×25 magnification and photographed with a digital camera.

2.6 Microscopic Raman spectroscopy

The microscopic Raman spectrum was measured using WorkStationTM manufactured

by Kaiser Optical Systems, Inc. (USA). The measurement conditions were as follows:

excitation laser wavelength: 785 nm, measurable wave number region: 150 to 2900

cm−1, exposure time: 5 seconds, number of integrations: 3 times, spectral resolution: 4

cm−1.

2.7 LF-Raman spectroscopy

6
 LF-Raman spectra were obtained using a Ondax THz-Micro® system manufactured

by Coherent Inc. (USA) with 976 nm excitation laser that included a SureBlock XLF

notch filter system attached to the WorkStationTM. The LF-Raman spectra were

measured using a spectral range that included both the Stokes and the anti-Stokes

scattering from -600 to +400 cm-1. Exposure times of 5 seconds and 4 cm-1 as spectral

resolution.

2.8 Powder X-ray diffraction

The PXRD of the felbinac drug substance was measured using Miniflex 600

(RIGAKU Co., Ltd., Japan). The measurement conditions were: X-ray source: Cu Kα (λ

= 1.5418 Å), voltage - current: 40 kV - 15 mA, scan axis: 2θ, angle range: 5–40°,

scanning speed: 20 °/min, speed step: 0.02°.

PXRD of the mock patch was measured using a fully automatic horizontal X-ray

diffractometer, SmartLab (RIGAKU Co., Ltd., Japan). The measurement conditions

were: X-ray source: Cu Kα (λ = 1.54186 Å), voltage - current: 45 kV - 200 mA,

incidentmirror: convergensmirror, scan axis: 2θ, angle range: 2-40 °, scanning speed:

3°/min, speed step: 0.01°. As mock patches for PXRD, felbinac was mixed with acrylic

polymer at a five-weight percent, and the release and support liner were changed to

polyimide film (Kapton® polyimide film, Toray DuPont). This was fixed to a sample

holder for measuring transmission while being sandwiched between polyimide films,

and was set in the PXRD instrument.

2.9 1H-nuclear magnetic resonance

7
 1
The H NMR spectrum was measured using a JNM-GSX400 (400MHz)

spectrophotometer (JEOL, Japan). In brief, 2 mg of felbinac and each acrylic polymer

(20, 40 and 100 mg) were dissolved in 1.5 mL of deuterated chloroform (Tokyo

Chemical Industry Co., Ltd.). The measurement conditions were as follows: number of

integrations: 100 times, measurement temperature: room temperature. Chloroform was

selected after considering the solubility of felbinac and the acrylic polymers in various

deuterated solvents.

2.10 Dissolution test

The dissolution test was conducted using NTR-3000 (Toyama Sangyo Co., Ltd.,

Japan) and DT126/128 light manufactured by ERWEKA GmbH (Germany). The

dissolution test conditions were as follows: method: paddle over disks with 100

rotations per minute, medium: 400 mL of the Japanese Pharmacopoeia dissolution test

solution 2 at 32°C. A paddle over disk (manufactured by Toyama Sangyo Co., Ltd.) was

compliant with USP Apparatus 5. The patches were punched out into a circle of 40 mm

in diameter, and the circular cut-outs were attached to a paddle over disk. The support

liner was covered with paraffin, and felbinac was dissolved from only the surface of the

adhesive layer. Ten millilitres of the test solution were collected at 15, 30, 45, 60, 90

and 120 minutes, and the same amount of test solution was replenished.

2.11 In vitro skin permeation test

The hairless mouse skin (Labo Skin Hos: HR-1, Hoshino Test Animal Co., Ltd.) was

set in a Franz-type diffusion cell. The patches were punched out into a circle of 12 mm

in diameter, and the circular cut-outs were attached to the kin of hairless mice to
8
evaluate skin permeation. The water bath temperature was set to 32°C. The Japanese

Pharmacopoeia dissolution test solution 2 was used as the receptor solution. The

receptor solution in the Franz-type diffusion cell was stirred using a stirrer bar at 600

rotations per minute. The test solution was collected by injecting 1 mL of the receptor

solution from the lower flow port and collecting 1 mL extruded from the upper flow

port. The test solution was collected at 0.5, 1, 2, 4, 5, 6, 7, 8 and 24 hours.

2.12 Measurement of felbinac content in the test solution

The felbinac concentration of the collected test solution was determined using a

liquid chromatograph, Agilent 1100 series (Agilent technology). The liquid

chromatography conditions were: the column: Inertsil C 8-3 (4.0 × 150 mm, GL

Sciences Inc.), the mobile phase: distilled water: acetonitrile: phosphoric acid (500: 500:

1), the flow rate: 1 mL/min, the detection wavelength: 254 nm.

2.13 Statistics

Parametric statistical tests (one-way between group analysis of variance, ANOVA and

tukey’s test) were used to investigate statistical differences. A probability of p<0.05 and

0.01 was considered statistically significant.

3. Results & Discussion

3.1 Preparation and observation of the mock patches

To elucidate an interaction between felbinac and components of the adhesive layer in

detail, mock patches were manufactured using three acrylic polymers, which were

different in substituent and physical properties. In addition, release and support liners of
9
the mock patches used were transparent films to facilitate the analysis for the molecular

state. Table 2 shows the determined amount of felbinac in the patches. The mock

patches were stored at room temperature and the status of API in the adhesive layer was

observed with polarized light microscope. There were a number of aggregated small

crystals in the AO polymer only, whereas no precipitation was observed in the AV1 and

AV2 polymers. The shape of precipitate in the AO polymer seemed to be different from

felbinac drug substance (Fig. 2).

3.2 State of API in each mock patch

We tried to identify the precipitates in the AO polymer using microscopic Raman

spectroscopy. Typically, more than three points of the AO mock patch were measured

for each component and confirmed to have the same spectra. As shown in Fig. 3a, the

precipitates were identified as felbinac from the Raman spectra of the precipitates in the

adhesive layer of AO patch which were consistent with the spectra of felbinac drug

substance. On the other hand, LF-Raman spectra of same precipitate, however, would

be different from that of felbinac drug substance. There appeared to be new peaks

around 29, 47 and 85 cm-1 instead of peaks around 44, 50 and 58 cm-1 observed in the

felbinac drug substance (Fig. 3b). Thus, the precipitated felbinac could be a polymorph

recrystallized in the adhesive layer of AO patch.

PXRD measurement was performed to confirm the crystal form of felbinac

precipitated in the AO mock patches. The release and support liner of the mock patches

had a large background, thus they were substituted to a polyimide film to obtain clear

PXRD patterns. As shown in Fig. 4, the felbinac crystals in the adhesive layer showed a

different diffraction pattern from the drug substance, namely the new diffraction peaks
10
were observed at 2θ= 18.8, 20.2 and 20.8°. From these changes in the LF-Raman

spectra and PXRD patterns, precipitated felbinac in the AO polymer could be crystalline

polymorph different from the drug substance. To the best of our knowledge, there is no

report on the polymorphism of felbinac, the crystals were considered to be a novel

crystal form.

Woods et al. reported that the vibrational modes in the region of 0 to 100 cm−1 are

generated by global fluctuations and phonons, while those in the region from 100 to 200

cm−1 are generated by localized intermolecular interactions in Terahertz spectroscopy

[23]. Therefore, the change of LF-Raman spectra, which was 0-100 cm-1, observed in

the AO polymer could be derived from a conformational transition and/or slight

displacement of felbinac molecule in the crystalline lattice.

PXRD measurement, which is widely used for identifying crystal forms, seemed to

have a limitation for evaluating crystalline components in adhesive layer of

pharmaceutical patches on the market. In addition, to isolate the crystals from the

adhesive layer were considered to be difficult for the patches with regard to technical

view point. Therefore microscopic Raman measurement in particular LF region was

considered to be a promising technique to elucidate the crystalline state of API in the

adhesive layer of patches.

3.3 Interaction between felbinac and acrylic polymers

The interaction between felbinac and each polymer was evaluated using 1H-NMR,

since the difference in interaction was estimated to be related to the propensity in

1
crystallization and its crystal form. The H-NMR spectra of felbinac and the

felbinac/polymer mixtures are shown in Fig. 5. In increasing the amount of polymer, the
11
chemical shift of carboxyl α-carbon proton (3.713 ppm) moved to higher magnetic field.

As shown in Fig. 5, the variation in chemical shift of polymer AV1 and AO were -0.062

and -0.014 ppm at the ratio of 50 times amount of polymer to that of felbinac,

respectively. The variation in chemical shift of AV1 with the five-membered lactam

ring was 5 times greater than that of AO with the carboxyl group. These polymers could

interact with periphery of felbinac carboxyl group.

Felbinac is known to form a dimer via association of the carboxyl group in the crystal

structure [24] (Fig. 6a). Although the dimer structure was estimated to be preferable

interaction also in a dissolved state, addition of polymers interfered the dimer formation

of felbinac by the intermolecular forces of functional substituent of polymers (Fig. 6b

and 6c). In the case of AV1 polymer, the obvious shift to higher magnetic field was

observed in the chemical shift of carboxyl α-carbon proton. AO polymer has also

carboxy group which can interact with felbinac similar to its dimer structure. On the

contrary, AV1 polymer has pyrrolidone substituent which could induce a protonation of

carboxy group in felbinac molecule resulting a localization of electron cloud and higher

shielding effect on the α-carbon proton. Thus it is suggested that the interaction with the

AV1 polymer was stronger than that of the AO polymer.

The crystallization behaviour of felbinac could depend on its saturated state in the

adhesive layer which was affected by the difference in interaction strength between

felbinac and the polymer. In the AV1 mock patch, felbinac was dissolved due to their

strong interaction without crystallization, whereas felbinac crystallized as new crystal

form in the AO patch. The intermolecular interaction of felbinac and AO polymer may

play a key role for the formation of the polymorph during crystallization.

12
3.4 Pharmaceutical properties of mock patches

The drug release behaviour and in vitro skin permeability of the mock patches using 3

kinds of polymers are shown in Fig. 7a and 7b. It was confirmed that the mock patches

made with AO polymer showed a higher dissolution rate and skin permeability than

those of mock patches prepared with AV1 and AV2 polymers significantly. The

permeation parameters of each mock patch are shown in Table 3. The flux and

cumulative permeation amount at 24 h (Q 24) of AO mock patch was 4.7-6.6 times and

4.7-6.6 times higher than that of those of AV1 and AV2 mock patches. On the other hand,

the lag time (T lag) of AO mock patch was 1-1.4 h shorter than that of AV1 and AV2

mock patches.

The two polymers, AV series, have same chemical structure including pyrrolidone

substituent, and different viscosities depending on their degrees of polymerization. As

mentioned above, both patches of AV series showed similar pharmaceutical

performance which was much lower than that of AO patch, thus their chemical structure

could be important rather than their viscosity. From the NMR study, the interaction

between felbinac and AV series would be higher than that of AO. Liu et al., reported that

the drug release from patch was certainly influenced by the interaction between API and

polymers in patches [25]. Therefore weak interaction could be superior for transdermal

dosage forms. These results suggest that the interaction depends on the combination of

API and polymers, hence a molecular state of API in transdermal dosage form should be

evaluated as well as pharmaceutical performance and then useful information can be

provided for better formulation design.

4. Conclusions
13
 In this study, the mock patches were prepared with three kinds of acrylic polymers

containing felbinac as model API to evaluate the correlation of pharmaceutical

performance and their intermolecular interaction. Crystalline state of felbinac in patches

can be clarified by microscopic observation, PXRD and Raman spectroscopy. In

particular, Raman Spectra in LF region was promising to detect slight change in crystal

form even in the patches. Finally, NMR spectroscopy was utilized to evaluate a

compatibility of API and polymers in context with pharmaceutical performance. These

results were consistent well and revealed that the comprehensive approach was useful to

understand the relationship of molecular state of API and pharmaceutical properties. We

hope the knowledge will be applied for development of adhesive base materials as well

as new drug products.

Acknowledgement

We would like to thank Daido Chemical Corporation for donating acrylic polymers,

3M Japan Limited for donating Release Liner and Polyester Liner, Rigaku Corporation

for help with powder X-ray diffraction measurement. Special thanks to Mr. Yosuke

Ozawa and molecular pharmaceutics laboratory members for helpful support and to Dr.

Hisashi Mimura for encouragement.

Declaration of competing interest

This work was funded by Daido Chemical Corporation.

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14
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19
 Table 1 Physicochemical properties of the acrylic polymers used in mock patches

Polymer Functional Appearance Viscosity

moiety (mPa∙s@25°C)
AO Acrylic acid / Octyl Carboxy group Clear 18,000
acrylate copolymer Ester linkage
AV1 2-Ethylhexyl acrylate / Lactam ring White 2,100
Vinylpyrrolidone Ester linkage
turbidity
copolymer
AV2 2-Ethylhexyl acrylate / Lactam ring Clear 13,500
Vinylpyrrolidone Ester linkage
copolymer

20
 Table 2 The amount of felbinac in mock patches

The amount of felbinac in a circle of 12 mm in Adjusted value (mg,

diameter (µg, for in vitro skin permeability test） for dissolution test)
AO 545.5 ± 32.77 6.06 ± 0.36
AV1 566.0 ± 50.10 6.29 ± 0.55
AV2 571.0 ± 24.67 6.34 ± 0.27

21
 Table 3 Skin permeation parameter of each mock patch

Flux (μg/cm2・h) T lag (h) Q24 (μg/cm2)

AO 2.95±0.16 0.04±0.45 69.23±4.21

AV1 0.45±0.06 1.46±0.41 10.54±1.42

AV2 0.63±0.10 1.18±0.25 14.71±2.34

22
 Fig. 1 Chemical structure

a) felbinac, b) AO polymer, c) AV1 and AV2 polymers

23
 Fig. 2 Polarization microscope observation

a) mock patches (×10 and ×25), b) drug substance (×25)

24
 Fig. 3 Raman spectra

a) Conventional region, b) Low frequency region

25
Fig. 4 PXRD pattern of the felbinac crystal in the AO mock patch and drug

substance

26
Fig. 5 1H-NMR spectrum of felbinac and the felbinac/polymer mixture

27
Fig. 6 Speculated molecular state of felbinac and intermolecular interaction

between felbinac and polymers

28
Fig. 7 Dissolution property a) and in vitro skin permeability b) of mock patches (*;

p<0.05, **; p<0.01)

29
Declaration of competing interest

This work was funded by Daido Chemical Corporation.