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Pharmaceutical Excipients and Tablet Coating Systems

Deliver. Protect. Stabilize.

· KlucelTM hydroxypropylcellulose · BenecelTM methylcellulose and hypromellose · AquariusTM coating systems · NatrosolTM hydroxyethylcellulose · AqualonTM ethylcellulose · Aqualon and BlanoseTM sodium carboxymethylcellulose Delivering pharmaceutical and nutraceutical performance since the 1950s

Immediate Release Binders Coatings

AquariusTM coating systems AqualonTM and BlanoseTM CMC NatrosolTM HEC BenecelTM MC and HPMC KlucelTM HPC AqualonTM EC

Modified Release Matrix Coatings

Rheology Control

Pharmaceutical Excipients

KlucelTM hydroxypropylcellulose

KlucelTM hydroxypropylcellulose (HPC) provides a remarkable set of physical properties for tablet binding, modified release and film coating. It is a surface active, thermoplastics polymer that is soluble in both aqueous and organic solvents. Low viscosity E, L, and ELF types are widely used for premier tablet binding with low use levels (2-6%). Additionally these grades provide improved adhesion and flexible coating applications. Regular particle size materials are used in wet processing and the X-grind material for dry processing. Many viscosity types are used for modified release matrix systems. Low molecular weight Klucel HPC polymers, due to their thermoplastic behavior and superior flow properties, find applications in melt extrusion. The PHARM grades of Klucel HPC comply with the monograph requirements of the National Formulary, European Pharmacopoeia and the Japanese Pharmacopoeia. Klucel HPC Grade (X = Fine) HF Pharm, HXF Pharm MF Pharm, MXF Pharm GF Pharm, GXF Pharm JF Pharm, JXF Pharm LF Pharm, LXF Pharm EF Pharm, EXF Pharm ELF Pharm Typical Brookfield Viscosity (mPa·s) 1,500 ­ 3,000 4,000 ­ 6,500 150 ­ 400 150 ­ 400 75 ­ 150 300 ­ 600 150 ­ 225 Solution Concentration 1% 2% 2% 5% 5% 10 % 10%

Controlled Release Matrix

Rheology Control

BenecelTM hydroxypropylmethylcellulose (HPMC) is widely used in the pharmaceutical industry due to their ability to thicken, bind and retain water; emulsify; suspend particulates; stabilize; and form films. These polymers are soluble in cold water and some mixed solvents, but insoluble in hot water due to thermal gelation. Benecel products are supplied as white to offwhite, free flowing powders. Controlled release (CR) grades have a fine , narrow particle size distribution that is optimized for hydrophilic matrix tablets. All Benecel products labeled with the "PHARM" or "PH PRM" suffix are compliant with the monograph requirements of the current editions of the National Formulary, the European Pharmacopoeia and the Japanese Pharmacopoeia.

Substitution Type Methylcellulose Hypromellose 2906 "F" Types Hypromellose 2910 "E" Types Hypromellose 2208 "K" Types Methylhydroxyethyl

1

BenecelTM HPMC Grade A15 LV PH PRM A15C PHARM A4M PHARM F4 PHARM E3 PHARM E5 PHARM E6 PHARM E15 PH PRM E50 PH PRM E4M PHARM1 E10M PHARM1 K100 LV PH PRM2 K250 PH PRM2 K750 PH PRM2 K1500 PH PRM2 K4M PHARM1 K15M PHARM1 K35M PHARM1 K100M PHARM1 K200M PHARM1 ME 50 PH PRM2 ME 350 PH PRM2 ME 233 P PHARM

2

Nominal Viscosity (mPa·s) 15 1500 4000 4 3 5 6 15 50 4000 10000 100 250 750 1500 4000 15000 35000 100000 200000 50 350 4000

X X X X X X X X X X X X X X

X X X X X X X X X X X

X X X X X X X X X X X X X

X X X X X X

CR grades available

Only CR grades available

To learn more about Ashland's pharmaceutical and nutraceutical products, please visit our website at ashland.com. To request literature or samples, please contact Ashland Aqualon Functional Ingredients Customer Service at 1-877-546-2782 or e-mail us at [email protected]

Capsules X

Coatings

Tablet Binder

BenecelTM hydroxypropylmethylcellulose

Pharmaceutical Excipients

AqualonTM and BlanoseTM carboxymethylcellulose

AqualonTM and BlanoseTM carboxymethylcellulose (CMC) is an anionic, water-soluble polymer. Typical uses for CMC are in (a) ointments, creams, and lotions, as a stabilizer, thickener and film-former, (b) jellies and salves, as a thickener, gelling agent, and protective colloid and film-former, (c) syrups and suspensions, as a thickener and suspending aid, (d) bulk laxatives, physiologically inert with high water-binding capacity, (e) mucoadhesives for its absorbency, (f) sustained release, as a thickener and diffusion barrier, and (g) tablet coating as a film-former. A variety of CMC grades are available, with varying degrees of substitution, viscosities and particle sizes. S-types provide smooth solutions, based on uniform substitution. O-types provide solubility and viscosity stability on storage in low pH media. Aqualon CMC grades and Blanose CMC grades designated P or PH are compliant with the monograph requirements of the European Pharmacopoeia and the National Formulary. Blanose CMC grades designated P or PH are compliant with the monograph requirements of the European Pharmacopoeia and the National Formulary. Aqualon CMC Degree of Substitution Viscosity and (mPa·s) High (1% concentration) 1500-3000 1000-2800 Medium (2% concentration) 1500-3100 800-3100 400-800 300-800 Low (2% concentration) 25-50 Extra Low (4% concentration) 50-200 Blanose CMC Degree of Substitution Viscosity and (mPa·s) High (1% concentration) 2500-4500 1500-2500 1000-2800 Medium (2% concentration) 1500-3100 200-800 400-600 Low (2% concentration) 50-100 25-50 7M1F PH 7LF PH 7M31F PH 7M8SF PH 7MF PH 9M31F PH 12M31P 12M8P 7H4XF PH 7HF PH 7H3SF PH 7HOF PH 9H4XF PH 0.7 0.9 1.2 7L2P 7LF PH 7MF PH 7M8SF PH 9M8F PH 9M31F PH 12M31P 7HF PH 7H3SF PH 0.7 0.9 1.2

Note: Fine (X) and coarse (C) particle sizes are available for several grades; please ask your local sales representative for more information.

To learn more about Ashland's pharmaceutical and nutraceutical products, please visit our website at ashland.com. To request literature or samples, please contact Ashland Aqualon Functional Ingredients Customer Service at 1-877-546-2782 or e-mail us at [email protected]

Pharmaceutical Excipients

AqualonTM ethylcellulose

AqualonTM ethylcellulose (EC) is soluble in a wide range of organic solvents. Typically, EC is used as a non-swellable, insoluble component in matrix or coating systems. EC can be used to coat one or more active ingredients of a tablet to prevent them from reacting with other materials or with one another. It can prevent discoloration of easily oxidizable substances such as ascorbic acid, allowing granulations for easily compressed tablets and other dosage forms. EC can be used on its own or in combination with water-soluble components to prepare sustained release film coatings that are frequently used for the coating of micro-particles, pellets and tablets. The improved compressible grade, Aqualon T10 EC, was developed with optimized compactibility (high ethoxyl content and low viscosity) and good powder flow (eliminating fine particle size via micronization). The PHARM grades of Aqualon EC are compliant with the monograph requirements of the National Formulary and the European Pharmacopoeia. Aqualon EC Grade T10 Pharm N7 Pharm N10 Pharm N14 Pharm N22 Pharm N50 Pharm N100 Pharm Typical 5% Brookfield Viscosity (mPa·s) 8 ­ 11 6­8 8 ­ 11 12 ­ 16 18 ­ 24 40 ­ 52 80 ­ 105 5% solution of 80/20 mixture of toluene/ethanol Ethoxyl Substitution 49.6 - 51.0 % 48.0 - 49.5 % 48.0 - 49.5 % 48.0 - 49.5 % 48.0 - 49.5 % 48.0 - 49.5 % 48.0 - 49.5 %

NatrosolTM hydroxyethylcellulose

NatrosolTM hydroxyethylcellulose (HEC) is a non-ionic water-soluble cellulose ether. Natrosol HEC is easily dispersed in cold or hot water to give solutions of varying viscosities and desired properties, though insoluble in organic solvents. It is used in (a) solutions and gels, to control rheology, providing thickening and pseudoplasticity, (b) emulsions, for high salt tolerance and surfactant compatibility, (c) modified release matrix tablets where highviscosity grades provides effective diffusion limiting release of drugs with low water solubility and (d) tablet coating where low viscosity grades impart flexibility to films while providing a good barrier to water and oxygen transmission. The PHARM grades of Natrosol HEC comply with the monograph requirements of the National Formulary and the European Pharmacopoeia.

Natrosol HEC Grade (X = Fine) HHX Pharm, HHW Pharm* HX Pharm, H Pharm M Pharm G Pharm L Pharm

Typical Brookfield Viscosity (mPa·s) 3,500 ­ 5,500 1,500 ­ 2,500 4,500 ­ 6,500 250 ­ 400 75 ­ 150

Solution Concentration 1% 1% 2% 2% 5%

* HHW Pharm is the finest particle size grade available. It allows for faster hydration and gel formation which controls initial "burst" effect.

To learn more about Ashland's pharmaceutical and nutraceutical products, please visit our website at ashland.com. To request literature or samples, please contact Ashland Aqualon Functional Ingredients Customer Service at 1-877-546-2782 or e-mail us at [email protected]

Aesthetic Coating

AquariusTM coating systems

AquariusTM coating systems, a family of dry, fully formulated film coatings systems are available for both pharmaceutical and nutraceutical solid-dosage forms. Aqualon formulators have access to an unrivaled range of cellulosic excipients, enabling Aquarius coating systems to be tailored to meet exacting requirements. Immediate release coatings provide the optimum balance of film strength and adhesion-even on challenging cores without impacting tablet dissolution. Most Aquarius coating systems are sprayable at 20% solids, which means faster throughput and reduced labor and energy costs compared to conventional, lower-solids coatings. Aquarius coating systems are available in clear, white, or full-color formulation systems to deliver a smooth, defect-free appearance with crisp logo definition. Color formulations are produced with the highest quality certified lakes, iron oxides, and natural colors. Aqualon can develop new colors or expertly provide a customer match using state-of-the-art color matching software. We use the appropriate compendial grades of raw materials that are suitable for the intended application.

Aquarius Coating Systems Product Line Summary Aquarius Coating Systems Name Ice Typical Ingredients Polymer HPMC HPC2 CMC3 MC4

1

Type Clear

Colorant None

Plasticizer Triacetin Polyethylene Glycol Glycerin None6 Triacetin Polyethylene Glycol Glycerin None6 Triacetin Polyethylene Glycol Glycerin None6

Weight Gain 0.25 ­ 1% · · · · · · · · · · · · · · ·

Advantages Excellentadhesion Superiordurability ExceptionalmoistureresistancewithHPC OutstandingglossespeciallywithCMC Sprayableat20%solids Brilliantwhite Highhiding Crisplogodefinition Superiordurability

White

Cool Vanilla Arctic White

HPMC1 HPC2

Titanium Dioxide

1 ­ 3%

Color

Various

HPMC1 HPC2

Titanium Dioxide FD&C Lakes D&C Lakes Iron Oxides Natural Colors5

3 ­ 5%

Sprayableat20%solids Excellentadhesion Crisplogodefinition Superiordurability Custommatchingavailable Formulatedtomeetmarketregulatory requirements · AsktoseeAquariuscolorkit

1 2 3 4 5 6

Hydroxypropylmethylcellulose (hypromellose). Hydroxypropylcellulose. Sodium carboyxmethylcellulose. Methylcellulose. Exempt from certification (CFR 21 Part 73). Using low glass transition temperature HPC can reduce or eliminate the need for plasticizer.

To learn more about Ashland's pharmaceutical and nutraceutical products, please visit our website at ashland.com. To request literature or samples, please contact Ashland Aqualon Functional Ingredients Customer Service at 1-877-546-2782 or e-mail us at [email protected]

Functional Coating

Sustained-release AquariusTM SRX coating systems are based on ethylcellulose (EC). These solvent-soluble systems, when coated onto drug-layered pellets, provide precise drugrelease profiles. Unlike aqueous dispersions, Aquarius SRX coating systems form coherent, durable films without curing. Aquarius SRX coating systems are available in three different porosity grades, with the option of further fine tuning the desired properties based on the formulation needs.

Aquarius® MG Moisture Guard Coating Systems High Efficiency, Label-Friendly Barrier Coatings for Hygroscopic Tablets

Type No Porosity Low Porosity High Porosity

Grade EX19093 EKX19102 EKX19103

Application Recommendations Highly soluble drug, 16 hrs + dissolution times High to medium soluble drug, 80% released in 10-16 hrs Medium and low soluble drug, 80% released in 3-12 hrs Elimination of burst effects in tablets

AquariusTM MG film coating systems

AquariusTM MG film coating systems are highefficiency, label-friendly moisture guard coatings for hygroscopic tablets. These cellulosic-based coatings provide superior barrier properties and shorter coating times. Aquarius MG film coatings are fully formulated, ready-mix systems that disperse quickly in water or solvent. The robust, flexible formulations can be customized based on color or plasticizer preference.

Tablets made with hygroscopic herbs, supplements, vitamins and API's often require a barrier coating which prevents adsorption of moisture from the atmosphere. This is particularly true for Milk thistle tablets coated with Aquarius MG coatings systems at climates with high humidity levels.

Figure 1. Milk Thistle Tablets coated with Aquarius MG at elevated humidity.

elevated humidity.

temp, 75% Coated with at roomUncoatedRH at room temp, 75% RH Coated after 48 hours spray rates Existing moisture barrier Aquarius MG PVA-based hours require low at room to systems are either after 48 which overcome tackiness or use hydrophobic components room at that reduce spray efficiency. temperature, temperature, use natural wax to provide 75% RH Aquarius MG coating systems are cellulosic-based coatings that 75% RH superior barrier properties & shorter coating times. These formulations provide:

Uncoated

Uncoated

Coated w/ Aquarius MG

Uncoated after 48 hrs

Coated after 48 hrs

· · · · ·

High-solids spraying: Clears (10-12%); Colors (20%) No tackiness ­ can use standard spray rates & process conditions to maintain high throughput All ingredients have FDA and EU direct food additive and/or Generally Recognized As Safe (GRAS) status Robust, flexible formulation that allows for changes in types of pigment, pigment level, type of plasticizer, and type of solution (aqueous or solvent) Fully formulated, ready-mix system that disperses quickly

Figure 2. Competitive Sorption Analysis - To simulate opening and closing a bottle in a high humidity environment, 400 mg copper sulfate tablets coated at 4% weight gain were exposed to alternating 5-hour periods of 90% and 0% relative humidity at 25°C under a nitrogen purge. Aquarius AMB showed the best performance.

100 10

TA Instruments Q5000 Sorption Analyzer

80 8

6

Opadry AMB

60

Sepifilm

4

Std White Uncoated

40

2

AQU D4289

20

0

0 0 5 10 15 20 25 30

Universal V4.4A TA Instruments

Time (hr)

For more information on custom Aquarius® MG coating systems, contact your AAFI sales representative or visit our web site at www.aqualon.com.

To learn more about Ashland's pharmaceutical and nutraceutical products, please visit our website at ashland.com. To request literature or samples, please contact Ashland Aqualon Functional Ingredients Customer Service at 1-877-546-2782 or e-mail us at [email protected]

Relative Humidity (%)

Weight Change (%)

Ashland Aqualon Functional Ingredients

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® Registered trademark, Ashland or its subsidiaries, registered in various countries TM Trademark, Ashland or its subsidiaries, registered in various countries * Trademark owned by a third party © 2010, 2011, Ashland PC-10641.2 250-72G 06-11

All statements, information and data presented herein are believed to be accurate and reliable, but are not to be taken as a guarantee, an express warranty, or an implied warranty of merchantability or fitness for a particular purpose, or representation, express or implied, for which Ashland Inc. and its subsidiaries assume legal responsibility.

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