Low-Substituted Hydroxypropyl Cellulose NF

Functional Disintegrant

CONTENTS PAGE

Introduction Description Manufacturing Process Variety of grades General properties Interactions with water Applications Disintegration and Compressibility Compatibility with active ingredients Anti-capping Direct compression Wet Granulation (high speed mixer) Wet Granulation (fluidizedbed) Pellet Extrusion Formulation Examples Bibliography Product Specifications

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INTRODUCTION

Introduction
L-HPC (Low-Substituted Hydroxypropyl Cellulose) was first approved in 1977 as a disintegrant for pharmaceutical dosage forms in Japan. A recent survey shows that L-HPC is ranked as the first choice of tablet disintegrant by Japanese pharmaceutical companies. The key benefits of L-HPC include: Excellent compatibility with active ingredients Disintegration into smaller particles leading to better dissolution Anti-capping effect for tableting process. Suitable for pellet extrusion as well as tableting. A variety of grades are available depending on application

This brochure briefly describes the properties of L-HPC. If you are interested in its characteristics and application, or have any questions, please contact us for further information.

DESCRIPTION
Trade name L-HPC

Generic name

Low-substituted hydroxypropyl cellulose

Abbreviation

L-HPC

IUPAC name

Cellulose, 2-hydroxypropyl ether (low substituted)

CAS registry number

9004-64-2

Compendial status (As of August 2005)

JP (Japanese Pharmacopeia) NF (US National Formulary) 21 CFR 172.870 (Code of Federal Register / Food Additive)

Structure

DESCRIPTION
4L-HPC vs. HPC

L-HPC is NOT the same as HPC. Although sharing the same CAS number, L-HPC has different characteristics from Hydroxypropylcellulose (HPC), a binding agent widely used for solid dosage forms. L-HPC and HPC have separate monographs in pharmacopeias. While the regular HPC has a large amount of hydroxypropoxy groups in the cellulose backbone, L-HPC has only a small level (See the picture below). Due to this chemical difference, HPC is soluble in water, but L-HPC is insoluble. HPC is typically used for granulation binder in an aqueous solution, but L-HPC cannot be used in this way. L-HPC is an effective disintegrant due to its swelling action in water, but this is not the case with HPC. Because L-HPC also has good compressibility, dry blending of this material produces hard tablets similar to those made from microcrystalline cellulose. In this application, L-HPC functions as a dry binder.

MANUFACTURING
The raw material of L-HPC is highly- purified wood pulp. L-HPC is manufactured under GMP* (Good Manufacturing Practices). Our plant facilities have been inspected by more than 50 customers throughout the world.

* Self-established excipient GMP based on the guideline proposed by IPEC (International Pharmaceutical Excipient Committee)

VARIETY OF GRADES

Currently six grades are commercially available. They have different particle sizes/shapes and chemical substitution levels. The numbers have variations depending on lot, grade, and determination method. See the following table. The following data shows only typical and approximate values. These are not specifications. For specifications, see page 20 of this brochure.

4Nomenclature

GENERAL PROPERTIES
Appearance True density Solubility White to slightly yellow powder 1.3 g/cm3 (measured with helium pycnometer) Not soluble in water or practical organic solvents. Swells in water. Soluble in 10 % NaOHaq., as a viscous and turbid solution.

Thermal degradation temperature

approx. 260 C

Equilibrium moisture content (25 C)

WaterSoluble Substances

INTERACTION WITH WATER

4Swelling property
L-HPC is not soluble in water. However, it absorbs water and significantly expands in volume. This swelling action causes tablets to quickly disintegrate. The swelling volume is dependent on particle size and hydroxypropoxy content, as shown below. This experiment was carried out using an apparatus shown on the right. For test formulation, disintegrant and alumina were blended 1: 4 to reduce the effect of strong binding between disintegrant particles. Compared to other excipients, L-HPC swells and reaches to its maximum volume quicker.

INTERACTION WITH WATER

4Water Uptake
This data shows water uptake through a bed of disintegrant powder using an apparatus shown below. Similar to the swelling property, the water uptake level depends on particle size and hydroxypropoxy content. Compared to the other super-disintegrants, L-HPC absorbs a great amount of water and reaches a plateau in a short time.

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4Effect of Test Fluid

Water uptake was tested using various test fluids. L-HPC shows pH-independent characteristics. In contrast, the behavior of ionic disintegrants was dependent on test fluids.
Test fluids: Purified water USP Simulated Gastric Fluid TS (pepsin absent), pH 1.2 USP Simulated Intestinal Fluid TS (pancreatin absent), pH 6.8

APPLICATIONS

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* If disintegration rate is not sufficient, try lower hydroxylpropoxy grades (i.e. LH-22 and LH-32). Performances are improved in some cases.

DISINTEGRATION AND COMPRESSIBILITY

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Comparing disintegration capability of various disintegrants, the ranking is dependent on active ingredient and formulation. Looking at the data shown below, L-HPC has similar disintegration capability to the other super-disintegrants. L-HPC also has a good compressibility compared to the other disintegrants.

COMPATABILITY WITH ACTIVE INGREDIENTS

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Because L-HPC is non-ionic, it is less reactive to active ingredients compared with ionic excipients. This excellent compatibility is the main reason for L-HPC being the first choice of Japanese pharma companies. For example, aspirin tablets with L-HPC were stable under high temperature whereas ionic ingredients showed whiskers of salicylic acid formed by hydrolysis (See picture below). Vitamin C tablets formulated with L-HPC showed no interaction compared with tablets using ionic disintegrants. The color stability was even better than with microcrystalline cellulose which is another non-ionic ingredient under the same moisture level. Our further study suggests that this was due to the low water activity of L-HPC because water molecules are bound to the amorphous region of the polymer. All tablets were made by direct compression.

ANTI-CAPPING
One of the benefits of L-HPC is to resolve capping, which is a typical problem in the tableting process. Several reports have pointed out that capping is caused by a high residual die-wall pressure during the tableting process. L-HPC reduces the residual die-wall force and ejection force during the tableting process. LH-11, the highly fibrous grade, is the most effective for anti-capping, as entangling of fibers is important for capping prevention.

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Anti-capping effect of L-HPC (Ethenzamide tablets) Tablets were prepared by direct compression. Excipients were added from 0 to 15 % in tablet. To measure capping number, 50 tablets were tested using a USP friabilator. They were rotated 750 times, and number of capped tablets was counted.

Residual die-wall force and ejection force were measured using a tableting process analyzer (TabAll Model N30-EX, Okada Seiko, Japan). L-HPC content: 20 %

The above results are considered to be due to entangling of L-HPC fibers. Compared with microcrystalline cellulose (MCC), fibrous structure can be seen in the cracking point of the L-HPC tablet (See the pictures on the right). Such structure enables tablets to resist against damaging forces from all directions.

DIRECT COMPRESSION
For direct compression, LH-21 is the primary grade to test. If you especially have a problem of capping, consider using of LH-11 (see page 14). If you need to use a large amount of L-HPC (more than 25 %), consider using LH-Bi (high density grade) for better flowability.

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Extreme case in direct compression (40% in the tablet) The performance of the existing products (LH-21) was the same or even better than that of standard grade of MCC (Avicel PH1O1). At higher speeds, LH-21 showed higher variation of the tablet weights. LH-B1 showed lower variations similar to a high density grade of MCC (Avicel PH302). Formulation: Spray dried lactose L-HPC Mg stearate 0.6 60 parts 40 Tableting: Laboratory scale rotary tableting machine (Vergo, Kikusui, Japan), 200 mg per tablet

WET GRANULATION (HIGH SPEED MIXER)

In wet granulation, L-HPC gives a buffer effect stabilizing the wet- massing process for a wide range of water content. LH-21 is typically used for this purpose. Especially for active ingredients with poor solubility and low wettability, you can use a higher amount of L-HPC to improve disintegration. Even as much as 20 - 40 % of L-HPC has been used in a tablet for this purpose. In spite of such a high content, stability problems are not significant as seen in other ionic disintegrants. In such applications, tablets disintegrate in very fine individual particles, so the dissolution is rapid and complete.

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WET GRANULATION (FLUIDIZED-BED)

In some cases a larger amount of L-HPC is needed to disintegrate and dissolve a poorly soluble drug. Because L-HPC is originally fibrous, the addition in a large amount may cause larger weight variation of tablets due to low flowability, or blocking of fluidization during the fluid-bed granulation. LH-B1, is designed to be non-fibrous and will be effective in such cases. Because this grade is not fibrous, there may be some limitation in compressibility.

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Formulation: Acetaminophen Lactose Cornstarch L-HPC Binder solution (5%-HPC)

40 parts 14 6 40 60

Fluid-bed granulation: Multiplex MP-01 (batch size 200 g) Inlet 60 C Outlet 30 - 35 t Spray rate 10 g/min

Tableting: Laboratory scale rotary tableting machine (Vergo Kikusui, Japan), 200 mg per tablet Pressure: 1 t (198 MPa) Speed: 40 rpm

PELLET EXTRUSION
As well as tableting, L-HPC is also applicable for pellet extrusion. Micronized grades (typically LH-31) are best suited for this application because smaller particles can easily pass through the screen. L-HPC provides wet mass with a buffer effect in which the wet mass accepts a wider range of water content. L-HPC plasticizes wet mass and shows greater productivity (extrusion speed and yield). The final pellets show quick disintegration and better friability compared with non-L-HPC formulations.

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L-HPC formulation: Aspirin L-HPC (LH-31) Hypromellose (Pharmacoat 603) Non L-HPC formulation: Aspirin Microcrystalline cellulose Croscarmellose sodium Hypromellose (Pharmacoat 603)

93% 5 2 93% 4 1

Process: Wet-massing Extrusion (DomeGran, Dalton, Japan, 1-mm screen) Spheronization Drying Sieving Friability test: USP Disintegration test: USP

FORMULATION EXAMPLES
4Multi-Vitamin Tablets (Direct Compression)

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The vitamins except ascorbic acid were blended as the master blend. An appropriate amount of the master blend, Vitamin C, L-HPC, lactose, and silicon dioxide were blended and passed through a #200 screen. The mixture was further blended with Mg stearate and compressed into tablets using a rotary tableting machine. The tablets were oblong shape (17.8 mm-L and 7.8 mm-W), and the main compression force was 3 tons (233 MPa). 4 Acetaminophen Tablets (rapid disintegration)

Results: Hardness: 25 kgf Disintegration time: 26 min Friability: 0.1 % Capping: none

Acetaminophen and L-HPC were blended and granulated in a high speed mixer, using water as the binding fluid. The wet mass was passed through a #18 screen and dried in an oven at 60t. The granules were passed through a #20 screen and blended with Mg stearate and talc, followed by compression using a rotary tableting machine (compression force: pre 0.3 t (22 MPa), main 1 t (74 MPa)). The tablet shape was flat and diameter was 13 mm.

Results: 6.1 kgf Hardness: Disintegration time: 22 sec

FORMULATION EXAMPLES
4Chlorphenesin Carbamate Tablets (Wet Granulation)

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The initial four ingredients were blended and granulated using a high speed mixer. Water (45 % with regard to the powder) was used as the binding fluid and the wet mass was passed through a 16-mesh sieve. The granules were dried in an oven at 40 C for 16 hrs. Silicon dioxide and LH-21 were added to the granules and blended for 20 mm., followed by 2-minute blending with Mg stearate. The granules were then compressed into tablets using a rotary tableting machine (compression force: pre 0.3 t (37 MPa), main 1.0 t (125 MPa); tablet diameter: 10 mm).

This original powder of chlorphenesin carbamate tends to stick on the turntable on the tableting machine, but the excipients added externally prevented the sticking problem, and the tabletting operation was carried out smoothly. 4Aspirin Pellets (Extrusion) - See also page 17.

The powder blend was wet-massed in a high speed mixer, using purified water (26 % with regard to the powder weight) as a binding fluid. The wet mass was passed through a screen (mesh size: 1 mm in diameter) using an extrusion machine. The extrudates were then spheronized using a spheronizer, and dried in a fluidizedbed (Inlet temp. 60 C)

BIBLIOGRAPHY
[Toxicology] H.Kitagawa, T.Tokunaga, S.Ebihara, H.Kawana and T.Satoh, Acute Toxicities of Hydroxypropyl Cellulose in Mice and Rats, Pharmacometrics, 4, 1013-1015, 1970. H.Kitagawa, H.Satoh, T.Yokoshima, T. Nanbo, K..Ushioda, T.Ueda and S.Oyabu, Absorption, Distribution, Excretion and Metabolism of 14C-Hydroxypropylcellulose of Low-substitution, Pharmacometrics, 12, 33-39, 1976. H.Kitagawa, H.Yano, H.Saito and Y.Fukuda, Acute, Subacute and Chronic Toxicities of Hydroxypropylcellulose of Low-substitution in Rats, Pharmacometrics, 12, 41-66, 1976. H.Kitagawa, H.Yano, H.Saito, M.Katoh, T.Makita and Y.Yashimoto, Teratological Study of Hydroxypropylcellulose of Low Substitution (L-HPC) in Rabbits, Pharmacometrics, 16, 259-269, 1978. H.Kitagawa, H.Yano, H.Saito, M.Katoh, T.Makita and Y.Yashimoto, Teratological Study of Hydroxypropylcellulose of Low Substitution (L-HPC) in Rats, Pharmacometrics, 16, 271-298, 1978. H.Kitagawa and H.Saito, General Pharmacology of Hydroxypropylcellulose of Low Substitution (L-HPC), Pharmacometrics, 16, 299-302, 1978. [Dust explosivity] H. Mukai, H. Muto, and Y. Onda, The dust explosivity of sevaral kinds of cellulose derivatives. J. Soc. Powder Technol., Japan, 32, 4-9 (1995) [in Japanese]. [Applications] Y. Kawashima, H. Takeuchi, T. Hino, T. Niwa, T. L. Lin, F. Sekigawa and M. Ohya, The effects of particle size, degree of hydroxypropyl substitution and moisture content of low-substituted hydroxypropylcellulose on the compatibility of acetoaminophen and the drug release rate of the resultant tablets. S.T.P. Pharma Sciences, 3, 170-177, 1993. S. Ueda, T. Hata, S. Asakura, H. Yamaguchi, M. Kotani, and Y. Ueda, Development of a novel drug release system, time-controlled explosion system (TES). I., Concept and design, J Drug Targeting, 2, 35-44, 1994. S. Ueda, H. Yamaguchi, M. Kotani, S. Kimura, Y. Tokunaga, A. Kagayama, T. Hata, Development of a Novel Drug Release System, Time-Controlled Explosion System (TES). TI. Design of Multiparticlulate TES and in vitro drug release properties. Concept and Design. Chem. Pharm. Bull. 42, 359-363,1994.

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S. Ueda, R. Ibuki, S. Kimura, S. Murata, T. Takahash, Y. Tokunaga, and T. Hata, Development of a Novel Drug Release System, Time-Controlled Explosion System (TES). III. Relation between Lag time and membrane Thickness. Chem. Pharm. Bull. 42, 364-367, 1994. S. Ueda, R. Ibuki, A. Kawamura, S. Murata, T. Takahashi, S. Kimura, and T. Hata, Development of a Novel Drug Release System, Time-Controlled Explosion System (TES). IV. In vivo drug release behavior. J. Drug Targeting, 2, 133-140, 1999. C-A. Scheef, D. Oelkrug, P.C. Schmidt, Surface acidity of solid pharmaceutical excipients III, Excipients for slid dosage forms. European J. Pharm and Biopharmaceutics, 46, 209-213, 1998. C. Alvarez-Lorenzo, J. L. Gomez-Amoza, R. MartinezPacheco, C. Souto, and A. Concheiro, Evaluation of low-substituted hydroxypropylcelluloses (L-HPCs) as filler-binders for direct compression. mt. J. Pharm., 197, 107-116, 2000. C. Alvarez-Lorenzo, J. L. Gomez-Amoza, R. MartinezPacheco, C. Souto, and A. Concheiro, The stability of theophylline tablets with a hydroxypropylcellulose matriz., Drug Dev md Pharmacy, 26, 13-20, 2000. T. Shimizu, Y. Nakano, S. Morimoto, T. Tabata, N. Hamaguchi, and Y. Igari, Formulation study for lansoprazole fasedisintegrating tablet. I., Effect of compression on dissolution behavior. Chem. Pharm. Bull., 51, 942-947, 2003. T. Shimizu, N. Kameoka, H. Iki, T. Tabata, N. Hamaguchi, and Y. Igari, Formulation study for lansoprazole fase-disintegrating tablet.II., Effect of triethyl citrate on the quality of the products. Chem. Pharm. Bull., 51, 10291035, 2003. T. Shimizu, M. Sugaya, Y. Nakano, D. Izutsu, Y. Mizuaki, K. Okochi, T. Tabata, N. Hamaguchi, and Y. Igari, Formulation study for lansoprazole fase-disintegrating tablet. IlL, Design of rapidly disintegrating tablets. Chem. Pharm. Bull., 51, 1121-1127, 2003.

PRODUCT SPECIFICATIONS

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Package

50 kg - Fiber drum with polyethylene double bag inside 1 kg - Polyethylene double bag

Shin-Etsu Chemical Co.,Ltd

Cellulose & Pharmaceutical Excipients Department

6-1, Ohtemachi 2-chome, Chiyoda-ku, Tokyo, 100-0004 Japan TEL: 8 1-3-3246-5261 FAX: 81-3-3246-5372 http://www.metolose.jp/e

05.8/1000