TYLOPUR

Hypromellose
TYLOPUR®

Content
Introduction 3

Description 4

Substitution Types and Major Applications 5

Physicochemical Properties 6

Applications 7

1. Low Viscosity Grades 8

a) Coating 8
I. Laboratory Scale Coating 8
II. Pilot Scale Tablet Coating 10
III. Logo Tablet Coating 10
IV. Pellet Coating 11
b) Granulation 13

2. High Viscosity Grades 15

a) Matrix Tablet 15
I. Solubility 16
II. HPMC Properties 16
III. Composition 18
IV. Preparation 19
V. Overview of HPMC Key Quality Attributes in Matrix Tablets 21

Product Specifications 22
1. Low Viscosity Grades 22
2. High Viscosity Grades 22

Packaging 24

Application Guide 25

2
Introduction
TYLOPUR® is Hypromellose (HPMC) and a versatile pharmaceutical excipient. TYLOPUR® is manufactured at Tyloshin 2
plant at SE Tylose GmbH & Co. KG in Wiesbaden, Germany. This plant operates under GMP conditions and fulfills the
requirements of the pharmaceutical industry. SE Tylose is a materials producer with an emphasis on a stable supply
of high-quality products.

One of TYLOPUR® applications is film coating and it is easy to use as a coating material to provide an excellent finish.
In addition, TYLOPUR® is effective as a granulation binder since it does not interact with drugs, has superior stability
and has a nonionic character. It is available in various viscosity grades for the granulation process.

TYLOPUR® can also be used as a hydrophilic matrix agent for sustained release tablets. The hydrophilic matrix system
is the simplest sustained release technology for oral dosage forms, consisting essentially of a drug and a water
soluble highly viscous polymer, such as hypromellose. Shin-Etsu has focused on controlled release technology and
found that by controlling the chemical and physical properties of the HPMC, a more reproducible drug release can
be achieved.

Another application of TYLOPUR® is to enhance the solubility of drugs, for example using solid dispersion technologies.
TYLOPUR® can also replace gelatine for hard shell capsule manufacturing because of its greater stability.

Shin-Etsu has application laboratories located worldwide and is able to offer you technical services. These
laboratories are continuously making valuable contributions to pharmaceutical technology; detailed technical data
is available and formulation advices can be offered. We can also provide you with Quality by Design (QbD) samples
for your development projects. Please contact your technical sales manager for further information.

3
TYLOPUR®

Description

Trade Name TYLOPUR®

Generic Name Hypromellose

(Hydroxypropylmethylcellulose)

Abbreviation HPMC

Chemical Name Cellulose, 2-hydroxypropyl methyl ether

CAS Registry Number 9004-65-3

Compendial Status USP (The United States Pharmacopeia)

EP (European Pharmacopoeia)
JP (Japanese Pharmacopoeia)

Structure
OR CH2OR
O
O
OR
OR
O
O
CH2OR OR
n

R = -H
-CH3
-CH2CH(CH3)OH

4
Substitution Types and Major Applications
The substitution type describes the amount of methoxy and hydroxypropoxy substituents on the cellulose backbone
of TYLOPUR® and is mentioned in the pharmacopeia monographs. TYLOPUR® includes several grades with different
kind of substitution, low viscosity and high viscosity grades.

TYLOPUR® Hypromellose
(USP/ EP/JP)

Low High
Viscosity Grades Viscosity Grades

Trade Name TYLOPUR® 603 TYLOPUR® 60SH TYLOPUR® 65SH TYLOPUR® 90SH-SR
TYLOPUR® 645
TYLOPUR® 605
TYLOPUR® 606
TYLOPUR® 615

Substitution Type 2910 2910 2906 2208

Viscosity Range 3 – 15 mPa·s 50 – 13 000 mPa·s 50 – 4000 mPa·s 100 – 100 000 mPa·s

Applications Tablet/Pellet Coating Thickening Thickening Sustained Release

Granulation Binder Suspending Suspending (Matrix Tablet)
Liquid and Semi-solid Liquid and Semi-solid

Table 1: Substitution types and major applications of TYLOPUR® grades.

For the complete specification, please see page 22.

5
TYLOPUR®

Physicochemical Properties
True Density
1.26 – 1.31 g/cm3 (measured with helium pycnometer)

Tapped Density
0.50 – 0.70 g/cm3

Equilibrium Moisture Content

The relationship between relative humidity and equilibrium moisture content of TYLOPUR® is shown in Figure 1 and
2. In Figure 1, Tylopur 606 (low viscosity) was compared with povidone (PVP) and hydroxypropyl cellulose (HPC),
and there is no difference between TYLOPUR® and HPC. In Figure 2, high viscosity TYLOPUR® with different
substitution were compared and no difference was found.

30 30
PVP
Equilibrium Moisture Content [%]

Equilibrium Moisture Content [%]

TYLOPUR 90SH-4000SR
25 HPC 25
TYLOPUR 60SH-4000
TYLOPUR 606
20 20

15 15

10 10

0 0
0 20 40 60 80 100 0 50 100
Relative Humidity [%] Relative Humidity [%]

Figure 1: Relative humidity and equilibrium moisture Figure 2: Relative humidity and equilibrium moisture
content of TYLOPUR® 606, PVP and HPC at 25 °C. content of TYLOPUR® 60SH and 90SH at 25 °C.

Molecular Weight Stability at Various pH Values at 20 °C

1000000 5000
Weight Average Molecular Weight [g/mol]

2 wt. % Aqueous Solution Viscosity [mPa∙s]

4000

100000 3000

TYLOPUR 90SH-4000SR
2000
TYLOPUR 60SH-4000

10000 1000
1 10 100 1000 10000 100000 0 2 4 6 8 10 12 14
Solution Viscosity [mPa∙s] Aqueous Solution [pH]
Figure 3: Viscosity versus molecular weight Figure 4: Effect of pH on viscosity for TYLOPUR®.

Equation: Mw = 40000 × (logη) + 880 × (logη)4

(GPC-MALLS technique).
TYLOPUR® maintains a constant viscosity over the pH
(η: solution viscosity).
range of 3-11. At pH out of this range, the viscosity will
be lower. If stored at low pH (acidic), viscosity will
gradually decrease due to depolymerization.

6
Applications
TYLOPUR® is soluble in water and mixed solvents. It may form lumps, which require a long time to dissolve, if it is added
to such solvents all at once. Therefore, TYLOPUR® should be dissolved according to the following procedures.

Dissolving in Water

Add all of the TYLOPUR® in about 1/3 of the water, previously heated to above 80 °C, while stirring well. Because
hot water is a poor solvent for TYLOPUR® a uniformly wet dispersion is obtained. Then, add cold water to make the
prescribed volume while stirring well. When the temperature of the water falls to below 30 °C, TYLOPUR® can
dissolves completely and the solution can be used as a coating fluid. If a high-power stirrer is used, TYLOPUR® can
be readily dissolved by adding it gradually to the water at below 30 °C with stirring. Care must be taken to avoid
bubble or foam formation.

At 6 – 10 % polymer concentration (viscosity less than 100 mPas) any formed bubbles disappear when the solution
is left to stand for several hours. Shin-Etsu Silicone KM-72 (Polydimethylsiloxane) from Shin-Etsu Chemical can be
employed as antifoaming agents.

Dissolving in Organic Solvents

Pour a prescribed volume of ethanol into a container and add all of the TYLOPUR® in it while stirring. When a uniform
dispersion is obtained, add methylene chloride gradually and stir gently to form a well-wetted dispersion as the
coating solution.

Although great care is taken to avoid any foreign material contamination, it is recommended to sieve the product
and/or filter the product solution before usage.

If difficulties arise concerning the dissolution apparatus, removal of bubbles from the coating solution or during the
filtration of solutions, Shin-Etsu can offer technical advice based on extensive experience and know-how.

7
TYLOPUR®

1. Low Viscosity Grades

a) Coating
Film coating is usually done with aqueous solutions rather than organic solvents, since the cost of the solvent is lower,
the cost of equipment is also lower (solvent recovery and disposal are simpler), and the process is safer (better working
environment, less risk of explosion and no need for treatment to remove residual solvents in preparations). Accordingly,
Shin-Etsu recommends coating with an aqueous solution. Machinery which offers a high drying efficiency and short
coating time is available. Some coating formulations using TYLOPUR® are given in Table 4.

In addition to those examples many coatings are available for particular purposes such as improving abrasion
resistance, printability, impact strength, masking color and/or taste, and flowability. Coating formulation and quantities
differ considerably depending on the purpose, and it is necessary to change the formulation of the coating solution,
the drying temperature and the operating parameters of the coating equipment on a case-by-case basis. Shin-Etsu
can provide technical advice on the suitability of various coatings.

I. Laboratory Scale Tablet Coating

Ibuprofen was granulated in a high shear mixer. For the formulation and process conditions please refer to the
granulation section of the brochure.

After granulation, tablets were produced according to the formulation (Table 2).

Material w/w [%] [mg/tablet]

1
Ibuprofen 80.00 200.00
1
L-HPC 21 15.00 37.50
® 1
TYLOPUR 606 1.00 2.50
L-HPC 21 3.00 7.50
Silicon dioxide colloidal 0.50 1.25
2
Magnesium stearate 0.50 1.25
1 2
granulated with water added before compression

Table 2: Formulation of ibuprofen tablets.

Tablets were produced with 10-13 kN compression force (9 mm, round, biconvex) on IMA Kilian Pressima.

Parameters
Tablet weight [mg] 250
Tablet hardness [N] 101
Friability [%] 0.5
Disintegration time [s] 228
Dissolution (>80%) [min] 10
Table 3: Analysis of ibuprofen tablets.

8
Tablets were coated in a pan coater with TYLOPUR® 606, 645, or 615 grade until 3% weight gain (2 kg batch size
each). The formulation of the coating solution is presented in Table 4, the process parameters are presented in
Table 5.

Material TYLOPUR® 606 TYLOPUR® 645 TYLOPUR® 615

w/w [%] w/w [%] w/w [%]
HPMC 9.35 11.05 6.75
Talc 2.72 0.99 2.85
TiO2 1.70 2.55 3.90
Pigment 1.36 1.22 0.15
PEG 6000 1.87 1.19 1.35
Water 83.00 83.00 85.00
Solid content 17 17 15
Table 4: Coating formulation with TYLOPUR® 606, 645 and 615.

Coating Parameters TYLOPUR® 606 TYLOPUR® 645 TYLOPUR® 615

Nozzle type Schlick 970 Schlick 970 Schlick 970
Nozzle pressure [bar] 0.65 0.65 0.65
Inlet air temp [°C] 80 80 80
3
Inlet air flow [m /h] constant constant constant
Tablet bed temperature pre-heating [°C] 40 40 40
Tablet bed temperature during coating [°C] 38 – 40 38 – 40 38 – 40
Spray rate [g/min] 4.3 – 6.1 4.2 – 5.9 4.5 – 6.4
Pan speed [rpm] 22 22 22

Table 5: Coating process parameters.

Parameters TYLOPUR® 606 TYLOPUR® 645 TYLOPUR® 615

coated coated coated
Weight [mg] 262.3 258.4 258.8
Disintegration time [s] 728 474 559
Dissolution (>80 %) [min] 10 10 10

Table 6: Analysis of coated tablets.

The analysis of coated tablets showed that all tablets release more than 80% of ibuprofen within the first 10 minutes
of the dissolution test (Table 6).

9
TYLOPUR®

II. Pilot Scale Tablet Coating

TYLOPUR® coating in pilot scale coating, performed in 15 kg batch size. Placebo tablets were coated with TYLOPUR®
605, 645, or 615. Coating parameters are presented in Table 7.

Coating Parameters TYLOPUR® 606 TYLOPUR® 645 TYLOPUR® 615

Nozzle type Schlick 930-33/7-1S14 Schlick 970 Schlick 970
Nozzle pressure [bar] 2.9 2.9 2.9
Inlet air temp [°C] 80 80 70
3
Inlet air flow [m /h] 400 400 400
Tablet bed temperature pre-heating [°C] 40 40 42
Tablet bed temperature during coating [°C] 35 – 40 35 – 40 37 – 40
Spray rate [g/min] 9 – 23 6 – 23 4 – 20
Pan speed [rpm] 11 5 (during 5 min) – 12 5 (during 5 min) – 13

Table 7: Tablet coating parameters of scale-up process.

III. Logo Tablet Coating

Logo caffeine tablets were coated in a pan coater with TYLOPUR® 606 grade until 3% weight gain. The tablet core
formulation is presented in Table 8 (tablet weight 240 mg with 8 mm diameter). Two coating formulations (with and
without lactose) were prepared (Table 9), and the process parameters are presented in Table 10.

Material w/w [%] Material F1 w/w [%] F2 w/w [%]

®
Caffeine 20 TYLOPUR 606 7.0 7.0
L-HPC LH-11 10 Lactose 2.1 –
MCC 102 30 TEC 2.1 –
Lactose 38.5 Table 9: Coating formulation.
SiO2 0.5
Magnesium stearate 1 1.0
Total 100
1
added before compression

Table 8: Tablet core formulation.

10
 120
Coating Parameters w/w [%]
100
Coating equipment Bosch Solidlab 1

Dissolution [%]
80
Batch size [g] 560
Inlet temperature [°C] 54 60

Product temperature [°C] 32 40

Outlet temperature [°C] 33 20

3
Airflow [m /h] 38 0
Drum revolutions [rpm] 20 0 15 30 45 60
Time [min]
Spray rate [g·min-1·kg-1] 8.9
Nozzle diameter [mm] 0.5 Figure 5: Dissolution of uncoated and coated tablets;

pH = 1.2, 750 mL, λ = 275 nm).

Spray pressure [bar] 0.7 according to USP (n=6, Apparatus 2, 50 rpm, 0.1N HCl
Formation air pressure [bar] 0.2

Table 10: Coating process parameters.

Coating with TYLOPUR® 606 does not change the dissolution profile. Coating of tablets with a logo is improved when
adding lactose to the coating formulation.

IV. Pellet Coating

Pellets offer a great flexibility in pharmaceutical solid dosage forms, from design and development point of view.
Successful film coating can be applied onto pellets due to their ideal spherical shape and low surface area-to-
volume ratio. TYLOPUR® 603 (HPMC 2910, 3 mPas) can be used for sub- or top/color-coating of functional coatings.
Paracetamol layered sugar pellets (#25-30, 0.595-0.707 mm) were coated according to the formulation presented in
Table 11. The coating process parameters for fluid bed pellet coating using a wurster setup with TYLOPUR® is
presented in Table 12.

Material w/w [%]

TYLOPUR® 603 7.0
Water 93
Total 100

Table 11: Coating formulation.

11
TYLOPUR®

Coating Parameters
Coating equipment Diosna Minilab XP
Batch size [g] 800
Atomizing air [bar] 1.0
Nozzle diameter [mm] 1.2
Inlet tempature [°C] 70
Outlet temperature [°C] 34 – 41
Product temperature [°C] 37.41
3
Airflow [m /h] 30 – 70
Spray rate [g/min] 7.1
Table 12: Coating process parameters.

Paracetamol pellets were coated up to 10 % polymer weight gain. An intermediate sample was collected at 4 %
polymer weight gain. After the process, dissolution testing according to USP was performed – Figure 6.

Figure 6: Dissolution of pellets; according to USP (n=3,

mL, λ = 280 nm).

Apparatus 1, 100 rpm, method B, 0.1N HCl pH = 1.2, 900

The uncoated paracetamol pellets show virtually the same dissolution as the pellets with 4 % and 10 % polymer
weight gain. Coating of paracetamol layered sugar spheres with TYLOPUR® 603 (hypromellose 2910, 3 mPas) up to
10 % polymer weight gain does not affect the dissolution of paracetamol from the pellets.

Summary

The coated tablets/pellets must release the drug in simulated gastric fluid. Moreover, it is essential that the drug is
dissolved in water and buffer solutions with various salt concentrations and pH values similar to those of simulated
gastric fluid. This is because the pH value of human gastric juice shows inter-individual variation depending on age,
constitution, etc., and the drug therapeutic effect is required to be maintained irrespective of such differences.
TYLOPUR® film has very favorable dissolution characteristics from this point of view, and this is one of the main
reasons why TYLOPUR® is widely used as a coating agent.

TYLOPUR® is an easy to use product to coat tablets and pellets without having a delayed release effect, and this
has also been demonstrated in the pilot scale coating experiment.

12
b) Granulation

TYLOPUR® can also be used as a binder for granulation. The fine particle size (average 50 – 70 µm) allows good
admixture with the vehicle (lactose/cornstarch). TYLOPUR® is effective for fluidized bed granulation and high shear
mixer granulation. Shin-Etsu recommends the use of TYLOPUR® for fine granules and tableting granules as a highly
stable binder, which does not interact with active substances.

Material High shear mixer Fluid bed Fluid bed

Ibuprofen 83.3 83.3 80.8
L-HPC 21 15.5 15.5 15.1
®
TYLOPUR 606 (added as 7% aq. solution) 1.2 1.2 4.0

Table 13: Tablet formulations.

Granulation Parameters
Equipment Glatt TMG 1-6
Granulating time [min] 6
Blade [rpm] 400 – 300
Chopper [rpm] 300 – 1500
Drying Parameters
Machine Diosna Minilab XP
Inlet temp [°C] 65
Air flow [m3/h] 40
Drying time [min] 18
Table 14: Granulation process parameters for High shear mixer.

Granulation Parameters 1 % TYLOPUR® 606 4 % TYLOPUR® 606

Equipment Diosna Minilab XP Diosna Minilab XP
Bowl [L] 3 3
Nozzle position / pressure 1.2 mm / 1.5 bar 1.2 mm / 1.5 bar
3
Air flow [m /h] 40 40
Inlet air temperature [°C] 65 65
Product temperature [°C]
– Warm up 31.0 31.0
– Granulation 25.5 28.3
– Drying 31.0 29.0
Spraying speed [g/min] 5.4 – 11 Up to 12
Filter pressure [bar] 1.5 – 2.0 1.5 – 2.0
Filter cleaning / Pause [s] 5 / 0.5 5 / 0.5
Process time [min]
– Granulation 20 85
– Drying 8 4

Table 15: Granulation process parameters for Fluidized bed.

13
TYLOPUR®

Figure 7: High shear mixer. Figure 8: Fluid bed granulation.

Parameters High shear Fluid bed Fluid bed

mixer 1% TYLOPUR® 606 4% TYLOPUR® 606
Bulk density [g/cm3] 0.48 0.41 0.30
Angle of repose [°] 44.4 46.4 44.4
Loss on Drying (LOD) [%] 1.2 0.5 1.1
Particle size (x50) [µm] 126 104 188

Table 16: Granules properties.

Figure 9: High shear granules. Figure 10: Fluid bed granules.

Summary

The fluid bed process produces granules with lower bulk density than the high shear mixer process. Upon increasing
the TYLOPUR® 606 content in the fluid bed granulation from 1% to 4%, the lowest bulk density and largest particles
were obtained. The angle of repose showed nearly no difference when different granulation methods are used.

14
2. High Viscosity Grades
a) Matrix Tablet

TYLOPUR® high viscosity grades such as the 60SH and the 90SH types can be used for hydrophilic matrix agent and
Shin-Etsu can also provide a tighter specification which is especially suitable for sustained release formulations.

The matrix system has several advantages:

– It is very simple and easy to establish a formulation.
– The tablet is completely dissolved and thus achieves good bioavailability.
– It is easy to control the dissolution profile by selecting a specific grade.
– The matrix tablet system is an economical method for obtaining controlled release products.

The dissolution steps of a matrix tablet is presented in Figure 11. HPMC matrix tablets hydrate to form a gel layer,
which regulates the drug release pattern. The most important aspect of this matrix system is the homogeneity of
the HPMC particle size distribution in the tablet as the selection of the substitution types will affect the initial wetting,
swelling, hydration and gel strength.

Initial Swelling Gel Formation Expansion / Erosion Dissolution

First stage Second stage

Frequently troubles are observed in the first stage.

Figure 11: Schematic dissolution of the matrix tablets.

Major factors for formulation of matrix tablets:

Solubility of the drug – Solubility in water pH dependency

HPMC properties – Substitution types of HPMC

– Viscosity of HPMC
– Particle size

Composition – HPMC content in the tablet

– Tablet size
– Other excipients

Preparation – Direct compression or granulation

– Compression force
– Tablet shape and size
– Coating

15
TYLOPUR®

I. Solubility

For a highly water-soluble drug (Paracetamol solubility is 14.0 mg/mL in water at 25 °C), drug release is regulated
by diffusion through the gel layer. In the first 30 minutes an excess amount of drug in the gel layer can be released.
For a poorly water-soluble drug (Ibuprofen solubility is 0.021 mg/mL in water at 25 °C), drug release is regulated by
erosion of the matrix tablet. The dissolution curve is comparatively linear as compared with highly soluble drugs.
The dissolution profiles are shown in Figure 12.

100
Material w/w [%]
80 Paracetamol or 79.5
release [%]

Paracetamol Ibuprofen granules 1

60
Ibuprofen
TYLOPUR® 90SH-4000SR 20.0
40 2
Magnesium stearate 0.5
1
20 Granules were prepared by wet granulation
2
added before compression
0 Compression: 12 mm, 500mg/Tab, 15 kN
0 2 4 6 8 10 12
Time [h]
Table 17: Tablet formulation.
Figure 12: Dissolution profiles of Paracetamol (high
solubility) and Ibuprofen (low solubility); according to

tested with 0.1N HCl pH = 1.2 at λ = 280 nm and ibuprofen

USP (n=6, Apparatus 2, 50 rpm, 900 mL; paracetamol was

was tested with phosphate buffer pH = 7.2 at λ = 221 nm).

II. HPMC Properties

Effect of Substitution Type

Substitution type of TYLOPUR® affects hydration speed of HPMC particles and gel strength, which can influence
the dissolution profile (Figure 13). Comparing the 60SH and 90SH-SR grades, a slower release is obtained when the
90SH-SR grade is used. In fact, the 90SH-SR grades were designed for the sustained release applications. The 60SH
grade has a significant higher methoxy content. A longer hydration time is required. This results in a longer time for
gel layer formation, giving initial faster dissolution.

100
Material w/w [%]
80 1
Paracetamol granules 79.5
release [%]

®
60 TYLOPUR 20.0
2
Magnesium stearate 0.5
40
1
60SH-4000 Paracetamol granules were prepared by
20 wet granulation; 2 added before compression
90SH-4000SR
Compression: 12 mm, 500 mg/Tab, 15 kN
0
0 2 4 6 8 10 12
Time [h] Table 18: Tablet formulation.

Figure 13: Effect of substitution type on the dissolution of

50 rpm, 0.1N HCl pH = 1.2, 900 mL, λ = 280 nm).

paracetamol tablets; according to USP (n = 6, Apparatus 2,

16
Viscosity Variation

Paracetamol tablets were prepared using different TYLOPUR® SR grades in order to evaluate their dissolution profile
(Table 19). The viscosity of HPMC affects gel strength, hydration speed in the first stage and erosion rate of the gel
in the second stage. The higher viscosity grade has stronger gel strength and slower dissolution – Figure 14.

120
Material w/w [%]
100
1
Paracetamol 52.4
80
release [%]

®
TYLOPUR HPMC 2208 varied 20
60
Lactose 27.1
40
2
Tylopur 90SH-100SR Magnesium stearate 0.5
20 Tylopur 90SH-15000SR
1
Tylopur 90SH-100000SR Paracetamol granules were prepared by wet
0
0 100 200 300 400 500 600 700 800
granulation; 2 added before compression
Compression: 18 mm x 9 mm (oblong), 1000 mg
Time [min]

Figure 14: Comparison of the dissolution profiles of Table 19: Tablet formulation.
TYLOPUR® SR with different viscosity grades; according

900 mL, λ = 280 nm).

to USP (n = 6, Apparatus 2, 50 rpm, 0.1N HCl pH = 1.2,

Effect of Dissolution Media

In order to see the impact of pH in dissolution profile, the paracetamol tablets were tested with different dissolution
media. The dissolution profile of paracetamol tablets was similar (Figure 15) in the different media, showing that the
dissolution profile is independent of pH.

100
Material w/w [%]
80 Paracetamol granules 1
79.5
release [%]

®
60 TYLOPUR 90SH-4000SR 20.0
2
Magnesium stearate 0.5
40
1
pH 1,2
Paracetamol granules were prepared by wet
20 pH 6,8 granulation; 1 added before compression
water Compression: 12 mm, 500 mg/Tab, 15 kN
0
0 2 4 6 8 10 12 Table 20: Tablet formulation.
Time [h]

Figure 15: Effect of different media on the dissolution of

paracetamol tablets; according to USP ((n = 6, Apparatus 2,
50 rpm, 900 mL).

17
TYLOPUR®

III. Composition

HPMC Content in Matrix Tablets

The content of HMPC in the matrix tablet has a significant effect on the dissolution profile. The HPMC content affects
the initial erosion of the tablet (first stage). Shin-Etsu recommends 20 % to 40 % content of TYLOPUR® SR for the
matrix tablet in order to obtain a delayed release (Figure 16).

100
Material w/w [%]
80 10% Ibuprofen granules 1
52.4
20%
release [%]

®
60 30% TYLOPUR 90SH-4000SR 10.0 – 40.0
40% Lactose 7.1 – 37.1
40 2
Magnesium stearate 0.5
20 1
Ibuprofen granules were prepared by wet
granulation; 2 added before compression
0
0 2 4 6 8 10 12 Compression: 12 mm,500 mg/ Tab, 15 kN
Time [h]

Figure 16: Effect of different HPMC content on the Table 21: Tablet formulation.
dissolution of ibuprofen tablets, according to USP

λ = 280 nm).
(n = 6, Apparatus 2, 50 rpm, 0.1N HCl pH = 1.2, 900 mL,

Fillers Consideration

Hydrophilic matrix tablet formulations require the API, the matrix polymer (HPMC 2208, TYLOPUR® SR) and the
lubricant. Fillers are added to achieve suitable tablet weight and modify compressibility and powder flow. Three
popular fillers are lactose, microcrystalline cellulose (MCC), and calcium phosphate. Depending on the nature of
the filler, different dissolution profiles are observed. The effect of the filler on the dissolution profile of matrix tablets
is different according to the dissolution media used. In case of acid media, MCC, as an insoluble filler, releases the
API slowest and soluble lactose is faster. In case of calcium phosphate, it is easily soluble in the acidic dissolution
media required by USP (0.1 N hydrochloric acid pH = 1.2) and releases the API fastest approaching zero-order re-
lease. In case of alkaline media, insoluble filler excipients like MCC or dibasic calcium phosphate anhydrous (practi-
cally insoluble at pH = 7.2), have a similar effect on the dissolution profile. On the other hand soluble lactose
increases the dissolution rate in comparison to MCC or dibasic calcium phosphate.

18
IV. Preparation

Direct Compression and Granulation

Hydrophilic matrix tablets are easily prepared with API and TYLOPUR® SR (Hypromellose 2208) by different methods
such as direct compression, wet granulation and dry granulation.

DC is the most cost-effective production method and can be applied if the other ingredients (such as API) have the
following properties:
– Sufficient flowability
– Sufficient compressibility
– Miscibility with TYLOPUR®

TYLOPUR® itself has sufficient flowability and compressibility to be used by DC. However, in some cases the other
ingredients do not have the desired properties to use the DC method. Instead, wet or dry granulation, with standard
equipments such as High Shear Mixer, Fluid Bed and Roller Compactor, should be used. For wet granulation, a
mixture of water and ethanol (20:80 by wt.) is recommended as a solvent.

Other Ingredients
Blending Compression
TYLOPUR® 90SH-SR

Figure 17: Direct compression.

Granulation Fluid
Other Ingredients
Granulation in Fluid Bed or
Compression
High Shear Mixer and Drying
TYLOPUR® 90SH-SR

Figure 18: Wet granulation.

Other Ingredients
Granulation in
Compression
Roller Compactor
TYLOPUR® 90SH-SR

Figure 19: Dry granulation – roller compaction.

19
TYLOPUR®

Example

Paracetamol Sustained Release Matrix Tablet by Direct Compression and Wet Granulation

DC is the simplest technique to prepare matrix tablets. It essentially consists of a drug and TYLOPUR®. Drug
substance, which usually shows poor flowability, is primarily granulated in a high shear granulator. With wet
granulation of API and excipients, a homogenous mixture is obtained and segregation can be avoided. Furthermore,
the flowability of the API is increased by wet granulation process.

Different TYLOPUR® SR grades are compared regarding their dissolution profile when prepared by DC or WG (Figure
20 and 21, respectively).

Material w/w [%] Material w/w [%]

1 1
Paracetamol granules 10.5 Paracetamol 10
® ® 1
TYLOPUR 90SH-SR 20 TYLOPUR 90SH-SR 20
1
Lactose 69.0 Lactose 69.5
2 2
Magnesium stearate 0.5 Magnesium stearate 0.5
Total 100 Total 100
1 1
Paracetamol granules were prepared by wet Granulated; 2 added before compression;
granulation; 2 added before compression Compression: 12 mm, 500 mg/Tab, 15 kN
Compression: 12 mm, 500 mg/ Tab, 15 kN

Table 22: Formulation of tablets prepared by direct Table 23: Formulation of tablets prepared by wet
compression. granulation.

120 120

100 100

80 80
release [%]

release [%]

60 60
®
TYLOPUR 90SH-100SR
40 40 TYLOPUR® 90SH-100SR
TYLOPUR® 90SH-4000SR
TYLOPUR® 90SH-4000SR
TYLOPUR® 90SH-15000SR
20 TYLOPUR® 90SH-100000SR
20 TYLOPUR® 90SH-100000SR

0 0
0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200
Time [min] Time [min]

Figure 20: Comparison of the dissolution profiles of Figure 21: Comparison of the dissolution profiles of
tablets prepared by DC; according to USP (n = 6, tablets prepared by WG; according to USP (n = 6,

λ = 280 nm). λ = 280 nm).

Apparatus 2, 50 rpm, 0.1N HCl pH = 1.2, 900 mL, Apparatus 2, 50 rpm, 0.1N HCl pH = 1.2, 900 mL,

With increasing viscosity, a slower dissolution is observed. The biggest difference in the dissolution profile of a
highly soluble API is observed upon changing from the 100SR to the 4000SR grade. TYLOPUR® is suitable for direct
compression and wet granulation. Figure 20 and 21 shows that the obtained dissolution profiles are comparable.

20
Effect of Compaction Force on Dissolution Profile

The paracetamol tablets were prepared using different compaction forces in order to see the impact of this factor
on dissolution profile (Figure 22).

100
Material w/w [%]
80 1
Paracetamol granules 79.5
®
TYLOPUR 90SH-4000 20.0
release [%]

60
2
Magnesium stearate 0.5
40
1
10 kN Paracetamol granules were prepared by wet
20 15 kN granulation; 2 added before compression
20 kN Compression: 12 mm, 500 mg/ Tab
0
0 2 4 6 8 10 12 Table 24: Tablet formulation.
Time [h]

Figure 22: Effect of different compression forces on the

dissolution of paracetamol tablets; according to USP

λ = 280 nm).
(n = 6, Apparatus 2, 50 rpm, 0.1N HCl pH = 1.2, 900 mL,

The compaction force has no effect on the dissolution profile of paracetamol tablets, all the three compaction forces
showed a similar dissolution profile.

V. Overview of HPMC Key Quality Attributes in Matrix Tablets

Lower HPO content – Decrease in initial erosion

– Faster drug release
– No effect on tablet hardness

Higher viscosity – Decrease in initial erosion

– Slower drug release
– No effect on tablet hardness

Bigger particle size or – Increase in initial erosion

higher bulk density – Faster drug release
– Lower tablet hardness

Increasing HPMC content – Decrease in initial erosion

(minimum recommend 20 %) – Slower drug release
– Higher tablet hardness

21
TYLOPUR®

Products Specifications
1. Low Viscosity Grades
General Name Hypromellose
Type 603 645 605 606 615 Method
Substitution Type 2910
Identification A. - E. 1 Conforms EP
Viscosity [mPas] 2.4 – 3.6 3.6 – 5.1 4.0 – 6.0 4.8 – 7.2 12.0 – 18.0 EP
pH 1 5.0 – 8.0 EP
Appearance of solution 2 Conforms EP
Loss on drying 1 Not more than 5.0 % EP
Sulphated ash /
Not more than 1.5 % EP
Residue on ignition 1
Heavy metals 1 Not more than 20 ppm EP
1
Methoxy content 28.0 – 30.0 % EP
1
Hydroxypropoxy content 7.0 – 12.0 % EP
1 2
Harmonized items among the USP, EP and JP Specific local attribute in EP

Table 25: Specifications of low viscosity grades of TYLOPUR®.

2. High Viscosity Grades

General Name Hypromellose
Type 60SH 65SH 90SH-SR Method
Substitution Type 2910 2906 2208
Description Conforms EP
Characters Conforms EP
Identification A.-E 1 Conforms EP
Viscosity [mPa∙s] 1 See table 27 EP
pH 1 5.0 – 8.0 EP
Appearance of solution 2 Conforms EP
Loss on drying 1 Not more than 5.0 % EP
Sulphated ash /
Not more than 1.0 % EP
Residue on ignition 1
Heavy Metals 1 Not more than 20 ppm EP
Methoxy content 1 28.0 – 30.0 27.0 – 30.0 22.0 – 24.0
Hydroxypropoxy content 1 7.0 – 12.0 4.0 – 7.5 8.0 – 12.0
1 2
Harmonized items among the USP, EP and JP Specific local attribute in EP

Table 26: Specifications of high viscosity grades of TYLOPUR®.

22
TYLOPUR® meets all the requirement for the EP Hypromellose (substitution type: 2910, 2906 and 2208), USP Hypromellose
and JP Hypromellose. Moreover, in addition to the tests prescribed in the aforementioned Pharmacopeias,
Shin-Etsu carries out tests for foreign matter contamination (including black specs), microbiological contamination,
yellowness index, etc., in order to ensure strict quality control. TYLOPUR® is manufactured in accordance with the
good manufacturing practice (GMP). A certificate of analysis (CoA) commonly incorporating test results on the EP,
are routinely attached to TYLOPUR® products. Quality specifications are shown in the tables 25 and 26.

Labeled viscosity Specification1 60SH 65SH 90SH 90SH-SR

●
[mPa∙s]

● ●
4 3.2 – 4.8

●
50 40.0 – 60.0

●
100 80 – 120

●
400 320 – 480

● ● ●
1500 1125 – 2100

●
4000 3000 – 5600

●
13000 7500 – 14000

●
15000 11250 – 21000
100000 75000 – 140000
1
Viscosity is measured with 2 % aqueous solution at 20 °C. Viscosity ranges are 80 % – 120 % of the nominal
value for samples with a viscosity less than 600 mPa.s and 75 % – 140 % of the nominal value for samples with
600 mPa.s or higher. Viscosity is hormonized item among the USP, EP and JP.

Table 27: Available grades and viscosity specifications.

23
TYLOPUR®

Packaging
Standard Package Customised packaging
Fiber drum (40-50 kg) with We can supply alternative packaging according to your
polyethylene single bag warehouse and manufacturing requirements.
inside.

40 -50 kg Fiber Drum 25 kg Fiber Drum 25 kg Carton Box Big Bag Type B
Ø 450 mm x h 740 mm Ø 375 x h 508 mm l 375 x w 375 x h 430 mm l 1060 x w 710 x h 1250 mm
(110 litres) (50 litres) (up to 1040 litres)

Packing option TYLOPUR® LV TYLOPUR® HV TYLOPUR® HV

●
60SH and 65SH 90SH-SR

●
25 kg Fiber Drum

●
25 kg Carton Box

● ●
40 kg Fiber Drum

● ● ●
50 kg Fiber Drum
Big Bag approx. 1040 L

Table 28: Summary of packing options.

Samples
All samples are packaged in a 1 L sample bottle (approx. 500 g).

Sample Bottle
(500 g)

24
Application Guide
TYLOPUR®
603 645 605 606 615 60SH 65SH 90SH-SR
Tablets
Film coating1
○ ○ ● ● ○
Binder solution
● ○ ○ ○
(wet granulation)

○ ○ ●
Sustained release
(matrix tablets)

● ○ ○ ○
Pellets
Film coating

● ● ● ○
Capsules
Capsule shell

● ● ● ○
Amorphous solid dispersion

● ● ● ○
Solvent free methods (HME)
Solvent methods

● ○
Liquids and others

○
Thickening

○ ○
Eye drops

● ○ ○ ○ ○
Suspending

○ ○
Dry syrup

○ ● ● ○ ●
Plaster/dermal patch
Oral strips
1
refers to a conventional water-soluble polymer coating ● = very suitable ○ = suitable
Table 29: Overview of the pharmaceutical applications with TYLOPUR® products.

For your specific application or further information, please ask your technical sales contact.

25
TYLOPUR®

Precautions for Safe Handling

Carefully read and understand the Safety Datasheet (SDS) before using this product!

PRODUCT INFORMATION
This substance is not classified as dangerous according Regulation 1272/2008 EC (CLP).
Normal safety precautions for handling chemicals must be observed.
This product does not contain any substance which may be considered hazardous to the health
and environmental to the current legislation.

HAZARDS IDENTIFICATION
The product can form flammable or explosive dust clouds in air!
It forms slippery surfaces with water.
Danger of slipping!

HANDLING AND PRECAUTION INFORMATION

Avoid dust formation.
Spilled product has to pick up mechanically under avoiding dust.
Do not breath dust.
Keep away from sources of ignition – No smoking!
The product is hygroscopic.
Protect from atmospheric moisture and water.

PERSONAL PROTECTION
If used properly, protective gloves are normally not required.
If used properly, no need to wear eye protection.
Wash hands before breaks and at the end of the work.
Do not breath dust! In case of insufficient ventilation, use filter apparatus, filter P1.

EMERGENCY AND FIRST AID PROCEDURES

After inhalation, take affected person into fresh air. Consult a physician.
After eye contact, rinse thoroughly with plenty of water, also under the eyelids.
If eye irritation persists, consult a specialist.
After ingestion, rinse mouth. If symptoms persists, call a physician.

STORAGE
Keep dry. Store away from excess heat and sunlight.
Store preferentially in original packaging.

DISPOSAL
Dispose of unused contents and container in accordance with all applicable federal, state and local laws.

26
Imprint
SE Pharma & Food Materials Distribution GmbH
Industriepark Kalle-Albert
Rheingaustraße 190-196
D-65203 Wiesbaden / Germany

The Manufacture of SE Tylose cellulose derivatives is based on the following registered international quality, environmental and energy
management standards.

Wiesbaden Plant ISO 9001 (01 100 84066) ISO 14001 (01 104 7041) ISO 50001 (01 407 7041) HACCP is applied to the relevant manufacturing facilities.
It is certified to Kosher and Halal.

All the information and data in this brochure are accurate and reliable to the best of our knowledge, but they are intended only to provide
recommendations or suggestions without guarantee or warranty. All of our products are sold on the understanding that buyers themselves will
test our products to determine their suitability for particular applications. Buyers should also ensure that use of any product according to these
data, recommendations, or suggestions does not infringe any patent, as Shin-Etsu will not accept liability for such infringement. Any warranty
of merchantability or fitness for a particular purpose is hereby disclaimed.

27
Information and Samples
For further information or samples, contact your local distribution partner or Shin-Etsu.

Europe India
SE Tylose GmbH & Co. KG Shin-Etsu Chemical Tylose India Pvt. Ltd.
Rheingaustr. 190-196, 65203 Wiesbaden, Germany Office No.B, 7th Floor, D Building, MBC Park,
Phone: +49 611 962-6204 Ghodbunder Road, Kasarwadavali,
Fax: +49 611 962-9777 Thane West-400615, Maharashtra, India
contact@SETylose.com Phone: +91 22 62833001
www.setylose.com pharmaindia@setylosein.com

North America South America

SE Tylose USA, Inc. Shin-Etsu do Brasil Representação
Pharmaceutical Application Laboratory de Produtos Químicos Ltda.
140 Commerce Way, Suite H, Rua Coronel Oscar Porto, 736,
Totowa, NJ 07512-1185, USA 11º Andar - Sala 114, Bairro Paraíso
Phone: +1 973-837-8001 CEP: 04003-003 – São Paulo, Brazil
Fax: +1 973-339-9094 Phone: +55 (11) 3939-0695
contact-pharma@setyloseusa.com Fax: +55 (11) 3052-3904
www.shinetsupharmausa.com Mobile: +55 (11) 99743-7557
max.ferrari@shinetsu.com.br
www.setylose.com

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