Bulletin 15: 2UDO6XVSHQVLRQV

The Specialty Chemicals Innovator

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Bulletin 15
Oral Suspensions

The Specialty Chemicals Innovator

Index
15.1 15.2 15.3 15.4 Basic Rheology Concepts Physical and Chemical Properties of Carbopol Polymers Carbopol Polymers for Oral Suspensions Benefits of Carbopol Polymers in Oral Suspension Formulations
15.4.1 15.4.2 15.4.3 15.4.4 Efficacy and Safety of Carbopol Polymers in Oral Suspensions Yield Value in Oral Suspensions Taste Masking with Carbopol Polymers Increasing Bioavailability in Oral Suspensions with Carbopol Polymers

15.5 15.6 15.7

Order of Addition Oral Suspension Troubleshooting Guide Oral Suspension References

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Oral Suspensions
Carbopol polymers have been used worldwide in oral suspensions for many years to thicken, modify flow characteristics, suspend insoluble ingredients, and to provide bioadhesion. These crosslinked polymers of acrylic acid provide excellent suspending ability for insoluble ingredients, and virtually eliminate the problem of settling, even when used at very low levels. Carbopol polymers swell when hydrated and neutralized, forming a colloidal dispersion. The insoluble ingredients in the suspensions are then permanently trapped in the interstitial spaces between the hydrogel particles.

15.1

Basic Rheology Concepts

Rheology is the study of how liquids flow. There are several key measurements of how well a liquid will suspend insoluble ingredients, namely yield value and viscosity. Yield value is the minimum amount of stress needed before flow begins. This property defines how well a liquid system can suspend insoluble drug actives and other solid particles. Unless the force of gravity operating on a suspended particle of a given mass exceeds the liquids yield value, the insoluble particles will not settle. Viscosity may be thought of as a measurement of the force per unit area required to maintain a certain rate of flow. Generally, the thicker the liquid, the higher the viscosity. (See Bulletin 12 for more background regarding suspension and flow properties.)

15.2

Physical and Chemical Properties of Carbopol Polymers

Carbopol polymers are very high molecular weight (over 3 billion Daltons) polymers of acrylic acid, crosslinked with polyalkenyl ethers. Each primary particle can be viewed as a network structure of polymer chains interconnected by crosslinks. Without the crosslinks, the primary particle would be a collection of linear polymer chains, intertwined but not chemically bonded. Carbopol polymers swell in water up to 1000 times their original volume (and ten times their original diameter) to form a gel when neutralized to a pH above 4-6 with a suitable base. Since the pKa of Carbopol is 60.5, the carboxylate groups on the polymer backbone ionize, resulting in repulsion between the negative particles, which adds to the swelling of the polymer. This results in a hydrocolloid suspension of Carbopol gels. The resulting formulation will have a large amount of swollen microgel particles, with interstitial spaces in which suspended particles are entrapped. Carbopol polymer microgels are easily moved by shear, but once the shear stops, the macro-gel structure immediately forms again. This enables highly viscous suspensions to be stirred or pumped easily, with instantaneous recovery once the stirring or pumping ceases.

15.3

Carbopol Polymers for Oral Suspensions

Noveon, Inc. currently promotes three Carbopol polymers for oral suspension applications. The original oral Carbopol polymer, Carbopol 934P NF has been used in oral suspensions worldwide since the mid 1960s. In the past ten years, Noveon, Inc. has designed two new products polymerized in ethyl acetate, as toxicologically preferred alternatives Carbopol 934P NF. Carbopol 974P NF has similar rheological properties to Carbopol 934P NF: both are highly crosslinked polymers which produce mucilages with very short flow rheology. Short flow rheology can be characterized as a gelled consistency similar to mayonnaise. Carbopol 971P NF, a lightly crosslinked polymer, provides very low viscosities and excellent yield values at low usage levels. Suspensions formed with Carbopol 971P NF will have longer rheology, and will flow like honey. Carbopol 71G, a granular form of 971P NF, will give the same viscosity and rheology, but is easier to handle and disperse.

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Table 15.3.1 Selecting the Proper Pharmaceutical Polymer

Noveon AA-1 USP 934 NF 934P NF 974P NF 971P NF 71G NF Carbopol 940 NF 980 NF 941 NF 981 NF 1342 NF 1382 Pemulen TR-1 NF TR-2 NF

Topical Gels Creams Lotions Oral Liquids Oral Suspensions Transdermals Bioadhesives

Figure 15.3.1 Thickening efficiency of Carbopol polymers in water (neutralized to pH 7.0 with NaOH)

15.4

Benefits of Carbopol Polymers in Oral Suspension Formulations

Carbopol polymers are most suited to aqueous formulations of oral suspensions, although elixirs with as much as 80% alcohol have been successfully formulated. Many commercial oral suspension products available today have been formulated with Carbopol polymers. They have numerous features which provide key benefits in oral suspension formulations:

Carbopol polymers are safe and effective in oral applications. Carbopol polymers have very high yield values, even at low concentrations. Carbopol polymers can mask the taste of certain bitter-tasting drugs. Carbopol polymers are bioadhesive, enabling increased bioavailability of oral suspensions. Carbopol polymer based suspensions are stable over a wide pH range. Carbopol polymers are stable to repeated freezing and thawing of a formulation, and to autoclaving. Carbopol polymers are approved by many of the worlds pharmacopoeiae, enabling ease of sale of a formulation worldwide.

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15.4.1 Efficacy and Safety of Carbopol Polymers in Oral Suspensions

Carbopol polymers have a long history of safe and effective use in commercial oral suspensions throughout the world, and are supported by extensive toxicology studies. In addition, there are a variety of literature references supporting the use of Carbopol polymers in oral suspensions. A partial listing has been provided for your reference in Section 15.7. For instance, M.M. Dolan and his group5 wrote a paper entitled Carbopol 934: An Improved Suspending Agent for Insoluble Test Compounds, in which the superior suspension capabilities of Carbopol 934 were demonstrated. Carbopol 934 provided the most uniform and permanent suspensions of those studied. The authors also wrote a commentary regarding the benefits they thought Carbopol 934 provided in oral suspensions: chemical stability; lack of support for fungal/bacterial growth; lack of interference with acute toxicity of pharmaceutical standards; and lack of interference with the therapeutic activity of drugs.

15.4.2 Yield Value in Oral Suspensions

Carbopol polymers are unique in that they provide a wide range of viscosity profiles and have very high yield values, even at very low concentrations. These combined features enable the formulation of oral suspensions that are stable permanently, with very low levels of polymer. Yield value is the more important of the two properties when determining suspending ability of a vehicle. This is demonstrated with a simple experiment. Carbopol polymers at a Brookfield viscosity of less than 2,000 cPs provide a permanent sand suspension, while locust bean gum, with a viscosity of nearly 23,000 cPs was only stable for eight hours. In a paper entitled Evaluation of Carbopol 934 as a Suspending Agent for Sulfadimidine Suspensions, B.M. 1 Berney and B. Deasy describe the small amount (0.3%) of Carbopol polymer required to form a permanent suspension of 10% sulfadimidine. The authors also describe their creep analysis studies, which showed that at 0.5% and 1% Carbopol polymer concentration, the suspension was a viscoelastic liquid, but that over 3% the suspension became a viscoelastic solid. As Figure 15.4.1 shows, Carbopol polymers are 10-50 times more efficient in delivering yield value or suspending ability than cellulosics or natural gums. The formulator can be highly confident that suspensions formed with Carbopol polymers will have excellent long term stability, as well as more consistency than those formed with natural suspending agents.

Figure 15.4.1 Comparison of yield values

Chemical Name Polyacrylic acid Polyacrylic acid Polyacrylic acid Carrageenan Carboxymethyl cellulose Xanthan gum Algin Magnesium aluminum silicate Acrylic emulsion Tragacanth gum Locust bean gum Guar gum Hydroxyethyl cellulose Hydroxypropyl methylcellulose Polyethylene oxide Fumed silica

Trade Name Carbopol 934 NF Carbopol 940 NF Carbopol 941 NF Carrageenan 231 CMC-7H Kelzan S Kelgin HV Veegum T Acrysol ASE-60 Traganth gum Locust bean 175 Galactasol 416 Natrosol Plus 430 Methocel J12MS Polyox WSR-301 Cab-O-Sil M-5

Supplier Noveon, Inc. Noveon, Inc. Noveon, Inc. FMC Corp. Aqualon Kelco Kelco R.T. Vanderbilt Rohm & Haas Rhone-Poulenc Rhone-Poulenc Aqualon Aqualon Dow Chemical Union Carbide Cabot Corp.

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15.4.3 Taste Masking with Carbopol Polymers

Oral liquid suspension systems have been successfully formulated using Carbopol polymers to mask certain bitter tasting active ingredients, enabling more pleasant tasting oral liquid suspensions to be formulated. In practice, the taste of an oral suspension is important to patient compliance. Two patents address the use of Carbopol 934P NF to mask the taste of 19 bitter tasting drugs. Hoffman LaRoches 1967 patent covers the reaction of Carbopol 934P NF with D-methorphan salt in water. This formulation is then dried to a powder, which is 20 essentially tasteless, and provides sustained release of the active. Abbotts 1991 patent covers the use of Carbopol to mask the taste of erythromycin and its derivatives in a palatable liquid dosage form. In this patent the drug and Carbopol polymer are mixed in an organic solvent and dried. The suspension is formed prior to ingestion by the patient.

15.4.4 Increasing Bioavailability in Oral Suspensions with Carbopol Polymers

Of additional interest are studies regarding the bioadhesive properties of Carbopol polymers. Certain research scientists have indicated that they have successfully used Carbopol in oral suspensions, and have found a significant increase in the bioavailability of their drugs. This may be due in part to Carbopols bioadhesive properties. Carbopol polymers form excellent bioadhesives for many reasons. Due to their chemical nature, these high-molecular weight polymers readily swell in water, providing a large adhesive surface for maximum contact with the mucin (the glycoprotein predominant in the mucous layer). Generally, polyacrylic acid polymers are understood to interact with the mucin, resulting in adhesion of the polymer to the mucin. Studies have shown that there is a marked increase in 10 mucous viscosity, and L.J. Kerr, et al describe the increase in the mucous microviscosity as well. These phenomena have been variously explained, and are thought to be the result of hydrogen bonding, chain entanglement of the two hydrogels, and/or surface effects. Once adhered, the Carbopol polymer based vehicle is highly resistant to being washed away. While there is a great deal of debate regarding the mechanism of bioadhesion, most scientists agree that bioadhesion is of interest because it increases the residence time of a dosage form at the absorption site, and thereby may result in increased drug bioavailability. One of the many papers written by Lehr or Junginger on the subject of Bioadhesion illustrates 11 this point. C.M. Lehr, et al discuss the possible advantages of using Noveon AA-1 USP polycarbophil as an oral bioadhesive in their paper entitled Oral Bioadhesive Drug Delivery Systems - Effects on G.I. Transit and Peptide Absorption.

Table 15.4.2

Carbopol Polymers in Oral Suspensions

Features
High yield value Polyacrylic acid chemistry Viscosity building Bioadhesion

Benefits
Suspension of actives and stable emulsion formation Masking of some bitter-tasting actives Rheology control Increased drug bioavailability resulting in potentially higher blood levels of the active compound

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15.5

Order of Addition
Depending on the solubility of the active ingredient to be incorporated, the following two methods are recommended: Insoluble Drugs For substances insoluble in water, slowly disperse the desired amount of Carbopol polymer in the water with the aid of high speed agitation (800-1500 rpm). To this dispersion add an aqueous solution of the neutralizing agent with slow speed agitation (500-800 rpm). Due to the high viscosity of the gel, high speed agitation would produce air entrapment and is not recommended. At this stage, the medicament may be incorporated into a semisolid base by use of mortar and pestle or an ointment slab by use of a spatula. Soluble and Semi-Soluble Drugs For soluble or semi-soluble substances, the medicaments may be dissolved or suspended in water before the neutralization of the polymer. Upon neutralization, a uniform dispersion of the medicament automatically results concurrent with gel formation. At times it may be necessary to vary the order of addition. For example, suspensions of agents such as calamine and zinc oxide can be made by first neutralizing the Carbopol gel and then adding the medicament to the sodium salt of Carbopol polymer.

15.6

Oral Suspension Troubleshooting Guide

If you are having problems formulating smooth or clear products, the following factors play a role in formulation: 1. Dispersing Techniques Carbopol polymers have a strong affinity for water. Supplied as dry powders, they are strongly hygroscopic. Similar to other hygroscopic powders, these polymers tend to clump or incompletely wet-out when improperly introduced to water or other polar solvents. Unlike other powders in which the clumps can eventually be reduced and dissolved, Carbopol polymer clumps are insoluble due to their formation of a water impermeable gel layer which prevents the wetting of the clump interior. Clumps of Carbopol polymers can be avoided by carefully wetting the individual polymer particles in ambient temperature water. This can be done by sifting the polymer into rapidly agitating water (800-1500 rpm). Production dispersing equipment, such as eductors or flocculent dispersers, as well as in-line mechanical powder dispersers are also effective. Once the polymer is wetted, reduce the rate of agitation to minimize air entrapment until complete hydration is achieved. The water vapor above preheated water can cause preswelling of the powder before it hits the water. Since this can cause gels to form, it is best to mix the polymer into cold water where possible. Bubbles can be avoided by reducing mixing speed (and repositioning the mixer) following powder dispersion to eliminate the liquid vortex. The persistence of a vortex in the liquid dispersion during high speed mixing will incorporate and entrap air. Lack of proper dispersion can lead to incomplete hydration of the polymer, resulting in broad pH or viscosity fluctuations or haziness in an oral suspension. See Bulletin 9 for more complete details on dispersing Carbopol-type polymers.

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2. pH The optimum pH range for a Carbopol polymers is 4-10. A pH above or below this range may result in variances in the formulation. 3. High Shear Mixing or Pumping Carbopol polymers stabilize a suspension by forming a gel matrix in which the soluble ingredients are trapped. High shear mixing, with colloid mills, homogenizers, etc., or high shear pumping can break down the hydrocolloid structure resulting in viscosity loss and potentially causing settling of the suspension. If homogenization is necessary, control formulation exposure by using an in-line homogenizer. Use low shear pumps, such as reciprocating diaphragm or auger/gear pumps. 4. Salt or Soluble Cations Carbopol polymers are sensitive to salts and cations, and use of products with greater than 0.1% of strongly ionizable salts should be minimized if possible. Use the acid, neutral or basic form of the drug whenever possible. Use deionized water. Add salts after neutralizing to determine their impact. Multivalent ions (Ca2+, Mg2+, Fe3+, Al3+, etc.) have the most serious effects and should be rigorously excluded. Transition metals (Fe, Cu, etc.) contamination causes a gradual viscosity reduction and may cause emulsion instability. Processing in stainless steel or nonmetallic equipment will minimize this effect as can the use of complexing agents such as EDTA. As a secondary measure, more Carbopol polymer may be used, or Carbopol 1342NF or Pemulen TR1NF may be used as these polymers are less sensitive to dissolved salts. 5. Incompatible Formula Ingredients Proteins, PVP polymers, polyethylene glycol (PEG), and polyethoxylated surfactants complex with unneutralized Carbopol polymers. Partially neutralize polymer prior to addition. 6. Insoluble Ingredients Carbopol polymers may not provide clear oral suspensions when insoluble ingredients are present. Solubilizing may reduce or eliminate this effect.

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15.7

Oral Suspension References

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Berney, B.M., Deasy, P.B., Evaluation of Carbopol 934 as a Suspending Agent for Sulfadimidine Suspensions, Int. J. Phar., 3(2-3), 73-80, 1979. Borodkin, P., Woodward, L., Li, P., Diesner, C., Harnandez, L., Vadnere, M., Lu, M.F., A Polymer Carrier System for Taste Masking of Macroglide Antibiotics, Pharmaceutical Research, 8(6), 1991. Briede, R.H., Application of Carbomer Water Gel 1%, Pharm. Weekbl., 118(9), 170-4, 1983. Delgado, A., Gallardo, V., Parera, A., Gonzalez-Caballero, F., A Study of the Electrokinetic and Stability Properties of Nitrofurantoin Suspensions. II: Flocculation and Redispersion Properties as Compared with Theoretical Interaction Energy Curves, J. Pharm. Sci., 79(8), 709-15, 1990. Dolan, M.M., Steelman, R.L., Tumilowicz, R.R., Carbopol 934: An Improved Suspending Agent for Insoluble Test Compounds, Toxicology and Applied Pharmacology, 2, 331-37, 1960. El-Assay, A.E.I., Hamza, Y.E., Halawa, E.E.A., Bioavailability of Hydrochlorothiazide Suspension, Drug Dev. Ind. Pharm., 11(1), 65-81, 1985. Fu Lu, M.Y., Borodkin, S., Woodward, L., Li, P., Diesner, C., Hernandez, L., Vadnere, M., A Polymer Carrier System for Taste Masking of Macroglide Antibiotics, Pharmaceutical Research, 8(6)1991. Gafitano, E., Popovici, I., Dorneano, V., Braha, S., Vasiliu, I., Studies on Upgrading of Liquid Pharmaceutical Preparation Formulas Containing Ethyl P-Aminobenzoate, Rev. Med.-Chir., 86(4), 665-68, 1982. Gallardo, V., Delgado, A., Parera, A., Salcedo, J., Electrophoretic Study of Nitrofurantoin in Aqueous Suspensions, J. Pharm. Pharmacol., 42(40), 225-29, 1990. Kerr, L.J., Kellaway, I.W., Rowlands, C., Parr, G.D., Proceedings of the Intl. Sym., Cont. Rel. Bioact. Mat., 17(122), 1990. Lehr, C.M., Bouwstra, J.A., Tukker, J.J., Verhoef, X.X., Deboer, A.G., Junginger, H.E., Oral Bioadhesive Drug Delivery Systems - Effects on G.I. Transit and Peptide Absorption, Pharm. Res., 7(9), September 1990 (suppl.) PDD 7226. Martin, E.W., Remingtons Pharmaceutical Sciences, Mack Publishing Company (Easton, PA) 13th ed., 239, 536-37, 1965. Meyer, R.J., Cohen, L., The Rheology of Natural and Synthetic Hydrophilic Polymer Solutions as Related to Suspending Ability, J. Soc. Cosmetic Chemists, presented November 1958, New York City, 1958. Patel, B.N., Hydrocolloids in Cosmetic and Pharmaceutical Dispersions, Second Part of the Series, Drug and Cosmetic Industry, 95(4), October, 1964. Ruiz, A., Parera, A., Martin, I., Effects of Alkaline Neutralizing Substances in Carbopol 934 Dispersions, Boll. Chim. Farm., 126(9), 368-75, 1987. Smart, J.D., Kellaway, I.W., Pharmaceutical Factors Influencing the Rate of Gastrointestinal Transit in an Animal Model, Int. Journal of Pharm., 53(1), 79-83, 1989. Soci, M.M., Parrott, E.L., Influence of Viscosity on Absorption from Nitrofurantoin Suspensions, Journal of Pharmaceutical Science, 69(4), 403-06, 1980. Swafford, W.B., Nobles, L.W., Some Pharmaceutical Uses of Carbopol 934, Journal of the American Pharmaceutical Association, 16(3), March 1955. U.S. Patent 3,346,449 assigned to Hoffman LaRoche, October 10, 1967. U.S. Patent 4,808,411 assigned to Abbott Laboratories, February 28, 1989. 7

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BULLETIN 15

Bulletin 15

The Specialty Chemicals Innovator

Worldwide Locations
HEADQUARTERS USA Noveon, Inc. 9911 Brecksville Road Cleveland, Ohio 44141-3247 Phone: 800.379.5389 216.447.5000 Fax: 216.447.5740 EUROPE Noveon Pharma P.O. Box 1151 83060 Raubling, Germany Phone: 49.8035.88.178 Fax: 49.8035.88.186

ASIA PACIFIC Noveon Asia Pacific Limited 2813-17 China Merchants Tower Shun Tak Centre 168-200 Connaught Road Central Sheun Wan, Hong Kong Phone: 852.2508.1021 Fax: 852.2512.2241

www.pharma.noveoninc.com

The information contained herein is believed to be reliable, but no representations, guarantees or warranties of any kind are made as to its accuracy, suitability for particular applications or the results to be obtained therefrom. The information is based on laboratory work with small-scale equipment and does not necessarily indicate end product performance. Because of the variations in methods, condi.

Noveon, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800-379-5389 or 216-447-5000

The Specialty Chemicals Innovator tions and equipment used commercially in processing these materials, no warranties or guarantees are made as to the suitability of the products for the application disclosed. Full-scale testing and end product performance are the responsibility of the user. Noveon, Inc. shall not be liable for and the customer assumes all risk and liability of any use or handling of any material beyond Noveons direct .

control. The SELLER MAKES NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. Nothing contained herein is to be considered as permission, recommendation, nor as an inducement to practice any patented invention without permission of the patent owner.

Trademark of Noveon, Inc. Copyright 2002 Noveon, Inc.

January, 2002