Polymers for Modifying Release 741 Hydrophilic Matrices

This section describes the critical quality attributes of polymers used in hydrophilic matrix systems. These are listed in Table 7.3 along with FDA-recommended maximum use levels [34]. Hypromellose (Hydroxypropyl methylcellulose)

Hydroxypropyl methylcellulose (HPMC) is widely used in matrix applications. Key advantages include global regulatory acceptance, stability, nonionic nature (resulting in pH-independent release of drugs), and ease of processing by direct compression (DC) or granulation. Other advantages are versatility and suitability for various drugs and release profiles (different viscosity grades being available) and extensive history of use. It is a mixed alkyl hydroxyalkyl cellulose ether containing methoxyl and hydroxypropyl groups. Type and distribution of the substituent groups affect physicochemical properties such as rate and extent of hydration, surface activity, biodegradation, and mechanical plasticity. Matrices exhibit pH-independent drug release profiles while aqueous solutions are stable over a wide pH range (3—11) and are resistant to enzymatic degradation.

HPMC is available commercially from the Dow Chemical Company as METHOCEL™. Four grades are available (A, E, F, and K) having differing hydroxypropoxyl and methoxyl substitutions.

Table 7.3 FDA registered oral formulations containing commonly used hydrophilic polymers [34]

Polymer/material Hydrophilic polymers Cellulosics Methylcellulose Hypromellose (hydroxypropyl methylcellulose, HPMC) Hydroxypropylcellulose (HPC) Hydroxyethyl cellulose (HEC) Sodium carboxymethylcellulose (Na-CMC) Noncellulosics: gums/polysaccharides Sodium alginate Xanthan gum

Locust bean gum (Ceratonia) Guar gum

Cross-linked high amylose starch Noncellulosics: others Polyethylene oxide (POLYOX™) Homopolymers and copolymers of acrylic acid

No of hits on FDA Maximum potency listed

Web pagea for oral formulations (mg)b

15 183.60

102 670.04

41 240.00

11 150.00

21 160.00

9 350.00

22 109.52

2 74.25

9 40.00

8 543.90

14 195.00c a Total number of listings on FDA web page for use in oral dosage forms b The "maximum potency" specifies the maximum amount of inactive ingredient for oral route/oral dosage form containing that ingredient. Listed potency is for generic material; refer to FDA web page for specific grade listing. Also the maximum potency number may be higher if its status showed pending status at the time of writing this chapter c Listing under poly(acrylic acid)

METHOCEL E (hypromellose 2910 USP) and K (hypromellose 2208, USP) are probably the most widely used grades in matrix formulations and are distributed worldwide by Colorcon Inc. The USP classification code is based on substitution. The first two digits represent the mean % methoxyl substitution and the last two the mean % hydroxypropyl substitution. HPMC is highly hydrophilic, hydrating rapidly in contact with water. Since the hydroxypropyl group is hydro-philic and the methoxyl group is hydrophobic, the ratio of hydroxypropyl to methoxyl content influences water mobility in a hydrated gel layer and therefore, drug release. METHOCEL grades for ER matrix formulations include E50LV, K100LV CR, K4M CR, K15M CR, K100M CR, E4M CR, and E10M CR. Viscosities of 2% aqueous solutions of these polymers range from 50 to 100,000 cPs at 20°C. Similar grades of HPMC are also available from suppliers such as Shin-Etsu Chemical Co., Ltd, Japan [35] and Ashland Aqualon Functional Ingredients [36].

HPMC exhibits glass transition temperatures, ranging from 160°C to 180°C depending on molecular weight and chemistry. It is classified as a nonthermoplastic material [37], thereby limiting its applicability in thermo-forming technologies such as hot melt extrusion or injection molding. Inclusion level can vary from 10 to 80%

of the total mass of the formulation, depending on the drug and desired release characteristics. A robust formulation with consistent performance and insensitivity to minor variations in materials or manufacturing processes may usually be obtained with a >30% (w/w) inclusion level [38-41].

Release rates from matrices depend on many interacting factors, such as polymer type and level, drug solubility and dose. Polymer:drug ratio, filler type and level, polymer:filler ratio, particle size of drug and polymer, and porosity and shape of the matrix are important [9, 42-57]. Hydroxypropyl Cellulose and Hydroxyethyl Cellulose

Hydroxypropyl cellulose (HPC) is a nonionic polymer, being a partially substituted poly (hydroxypropyl) ether of cellulose. It is available from Ashland Aqualon Functional Ingredients under the brand name of Klucel in different grades with differing solution viscosities. Molecular weight ranges from ~80,000 to 1,150,000 [36, 58]. High viscosity grades of HPC (e.g., Klucel HXF with fine particle size, 1,500-3,000 mPa of 1% solution) are generally used. Other high viscosity grades of HPC are also available from Nisso, namely, HPC-M and HPC-H (150-4,000 mPa of 2% solution) [59].

Inclusion levels can vary from 15 to 40%. Addition of an anionic surfactant (e.g., sodium lauryl sulfate) reportedly increases HPC viscosity and as a consequence reduces drug release rate [58, 60]. Combinations of HPC and other cellulosic polymers have been used to improve wet granulation and tableting characteristics and better control of drug release [58].

HPC is thermoplastic and its presence may enable processing of HPMC-containing formulations using hot melt extrusion or injection molding. It is not widely used because of its low swelling capacity and sensitivity to ionic strength of the dissolution media [61-65]. Gel strengths of HPC matrices decrease during dissolution, leading to less cohesive gel structures [61]. The lower tablet gel strength (G) of HPC matrices, compared to HPMC can cause poor in vitro/in vivo correlation [65].

Hydroxyethyl cellulose (HEC) is also a nonionic, partially substituted poly (hydroxyethyl) ether of cellulose. It is available in several grades from Ashland Aqualon Functional Ingredients under the brand name of Natrosol®. These vary in viscosity and degree of substitution [36]. High viscosity grades of HEC (1,500-5,500 mPa of 1% solution) are sometimes used in ER formulations. Typical inclusion levels are 15-40% of the total formulation mass. Swelling of HEC matrices has been reported to be considerably greater than HPC matrices. HEC matrices also exhibited relatively higher erosion rates, t50% (time to 50% release) being shorter for HEC than for HPC matrices [66]. In contrast to its widespread use in pharmaceuticals, HEC is not currently approved for use in food products in Europe or the USA. This restriction is due to the high levels of ethylene glycol residues that are formed during its manufacture [67]. Sodium Carboxymethylcellulose

Sodium carboxymethylcellulose (Na CMC) is an anionic, water-soluble polymer, prepared by reacting cellulose with sodium monochloroacetate. Various viscosity grades are available, reflecting degree of substitution. Aqueous solutions are stable over the pH range 4-10, precipitation occurring below pH 2: solution viscosity decreases rapidly above pH 10. Generally, solutions exhibit maximum viscosity and stability at pH 7-9. At pH 4.5 and 6.8 matrices containing Na CMC exhibit the morphology of a swellable matrix. The macromolecular chains in the gel network are held together by weak bonds resulting in erosion-mediated drug release. At pH 1.0 in contrast, the gel layer is rigid, typical of a partially cross-linked hydrogel, resulting in diffusional release [68]. Such sensitivity to dissolution media pH is attributable to the ionic nature of the polymer. Hence, release mechanisms may be sensitive to media pH.

Na CMC has been used in blends with HPMC to prepare hydrophilic matrices [68-70]. Mixtures of Na CMC and HPMC in dilute solution exhibit higher-than-expected viscosities. This may be attributable to intermolecular cross-links between carboxyl and hydroxyl groups. Baveja et al. advocated combining HPMC with Na CMC to provide zero-order release profiles for propranolol, metoprolol, oxpre-nolol, and alprenolol [69]. They hypothesized that the polymer combination syner-gistically increased viscosity, allowing erosion at a rate determined by the transitioning of the front between glassy and the rubbery polymer states. It was later established that viscosity enhancement was not solely responsible for modulating drug release: Complex formation between the anionic polymer and cationic drug also played a role [71].

Aiman and coworkers showed that erosion-mediated release rate of dextrometho-rphan from matrix tablets containing Na CMC was significantly lower than from HPMC-containing matrices. Release was also pH sensitive. The slower release was attributable to drug/Na CMC complex formation [72]. Matrices comprising HPMC/ Na CMC mixtures exhibited zero-order release profiles [69, 70]. Thus, pairing Na CMC with water-soluble basic drugs may have complex effects on drug release. For less soluble drugs, which are released principally by erosion, the above-reported effect appears to be reversed. A commercially available metformin hydrochloride ER tablet (Glucophage® XR, Bristol Myers Squibb) is reported to comprise a HPMC/Na CMC matrix to attain the desired release profile [73]. Sodium Alginate

Sodium alginate, a water-soluble salt of alginic acid is a natural linear unbranched polysaccharide extracted from marine brown algae. It consists of different proportions of a-D-mannuronic acid (M) and b-L-guluronic acid (G) units. The M and G units are 1 ® 4 linked by glycosidic bonds, forming homopolymeric M- or G-blocks and heteropolymeric MG blocks [74]. Matrices incorporating either a single alginate salt or combinations of salts have been employed to sustain release in vitro and in vivo. Commercially, sodium alginate for ER applications is available from FMC under the brand name Keltone®. Grades LVCR, LKX, and HVCR are generally used [75].

The presence of carboxylate groups that can accept or release protons in response to pH changes makes sodium alginate pH sensitive. At pH values below the pKa of the M (3.38) and G (3.65) monomers, the soluble sodium salt is converted to insoluble alginic acid. In a matrix tablet, sodium alginate pH sensitivity would affect the characteristics of the diffusion barrier and as a consequence drug release. Cryogenic electron microscopy reveals the hydrated surface layer formed by sodium alginate matrices in simulated gastric fluid to be particulate and porous, contrasting with the highly hydrated continuous gel layer formed in simulated intestinal fluid [76]. This difference in diffusion barrier properties affects hydration, swelling, and erosion kinetics leading to pH-dependent drug release. Cationic drugs (e.g., lidocaine) are released more slowly than anionic drugs (e.g., sodium salicylate), probably because of drug-polymer ionic interactions [77].

Matrices of sodium alginate are prone to lamination and crack formation at low pH (<3) which could result in "burst" release in the gastric environment [78, 79]. Crack formation does not occur in neutral environments. Such cracking can limit the use of sodium alginate in matrices because of the risk of dose dumping. However, its use may be facilitated by blending with HPMC, thereby obtaining a pH-independent release profile for basic drugs [80, 81].

Sodium alginate precipitates as alginic acid at low pH. The acid appears to confer a firm structure to the gel, reducing erosion. If drug solubility at this pH is high, diffusion through the gel matrix layer predominates as the release mechanism. At higher pH the alginate remains as the soluble salt, providing less resistance to erosion. This is likely to increase release rate. Such an effect can be beneficial for drugs whose solubility is lower at higher pH. Increased polymer erosion at such higher pH could compensate for the fall-off in driving force for diffusion/dissolution-mediated release as drug solubility decreases. An appropriate balance needs to be determined for each drug candidate. Verapamil hydrochloride ER matrices (Calan®SR, Pfizer) contain a combination of HPMC and sodium alginate to produce the desired drug release profile in vivo [82]. Xanthan Gum

Xanthan gum is an anionic high molecular weight polysaccharide produced by fermentation by the microorganism Xanthomonas campestris. Solutions exhibit weak gel-like properties at low shear rates. It does not form true gels at any concentration or temperature but can produce near zero-order drug release kinetics. Fickian diffusion was dominant during early dissolution of diclofenac minimatrices; erosion predominated during the later stages, suggesting that zero-order release was attainable. Rate of drug release is slowed by decreasing particle size of the polymer or increasing its concentration. Release is slightly faster in acidic media due to more rapid initial surface erosion. In tablets containing a large inclusion level of drug (50% theophylline), 20% xanthan gum proved to be an efficient release modifier but catastrophic failure occurred at 15% inclusion level [83].

Rheologically, xanthan gum exhibits rapid and marked shear thinning. In vitro drug release can depend somewhat on rate of agitation of the dissolution medium [83, 84]. Drug release was also found to be influenced by the ionic strength of the medium, particularly at ionic strengths similar to those in the GI tract. Thus, differences in GI fluid composition could affect in vivo performance. Commercially, xan-than gum is available from CP Kelco under the brand name of Xantural® [85]. The fine particle size grade of Xantural 75 (viscosity of 1,200-1,600 mPa) is generally recommended for use in ER formulations.

Combinations of xanthan gum with HPMC can retard drug release compared to single polymer systems. Such combination can also overcome the limitations of individual matrices. HPMC forms firm gels but does not hydrate as quickly as xan-than gum. However, xanthan gum does not form strong gels around a hydrating matrix and requires high concentrations to prevent rapid erosion. A combination of polymers may be more suitable for formulating ER matrices of high-solubility, high-dose drugs [86]. In such systems, the initial burst release, typical of high solubility drugs, is controlled by rapid gelation of the xanthan gum. Subsequent release and matrix integrity is maintained by the firm gel structure of HPMC.

The quick gelling property of xanthan gum has also been exploited in gas generating gastroretentive matrices of ciprofloxacin formulated with HPMC [87]. The instant viscolyzing behavior of xanthan gum enabled the entrapment of gas (carbon dioxide, formed by interaction of sodium bicarbonate in the matrix with the hydrochloric acid in the dissolution medium). Hydration and gelation of HPMC reduces the density of the formulation to provide early buoyancy for gastroretention. The subsequent hydration and firm gel layer formulation by HPMC further reduces bulk density, improving buoyancy and prolonging gastroretention. Carbomers

Carbomers are synthetic high molecular weight polymers of acrylic acid that are cross-linked with either allyl sucrose or allyl ethers of pentaerythritol. They are commercially available from Lubrizol under the brand name of Carbopol® and are available in grades that vary in viscosity, polymer type, and polymerization solvent [88]. Being cross-linked, these polymers are not water soluble but are swellable and gel forming. Swelling and gel formation behaviors differ somewhat from other hydro-philic polymers like HPMC, where swelling follows polymer hydration, leading to relaxation of polymer chains and their subsequent entanglement (physical cross-linking) to form a viscous gel. With acrylic acid polymers, surface gel formation is not due to polymer chain entanglement (the polymers are already cross-linked) but to formation of discrete micro gels comprising many polymer particles [40].

Erosion, as occurs with linear polymers like HPMC does not occur because of the water insolubility. Instead, when the hydrogel is fully hydrated, osmotic pressure from within breaks up the structure, sloughing off discrete pieces of the hydrogel. The hydrogel remains intact and drug continues to diffuse uniformly through the gel layer.

In contrast to linear polymers, higher viscosity does not result in slower drug release. Lightly cross-linked polymers (lower viscosity) are generally more efficient in controlling release than highly cross-linked variants [89].

Release from carbomer matrices may depend on the pH of dissolution media, because of the anionic nature of the polymer (p^a 6 ± 0.5) [90]. Swelling and gel formation are pH dependent. At lower pH the polymer is not fully swollen and drug release is faster. As pH increases the polymer swells and rapidly forms a gel layer, prolonging drug release. Carbomers, being anionic may form complexes with cat-ionic drugs depending on drug properties such as pKa, solubility, amine group strength, steric orientation, molecular weight and size.

It has been reported that carbomer inclusion levels of about 30% produce comparable drug release profiles to HPMC in both water and 0.1 N HCl. Release was slower in pH 6.8 phosphate buffer. Carbomer matrices also exhibited significantly lower gel strengths compared to HPMC matrices in all three media. This has been postulated as the reason for their significantly faster drug release in vivo compared to HPMC matrices [65].

HPMC/carbomer matrices have been explored for controlling the release of various drugs [88, 91, 92]. Advantages include low inclusion levels, versatility in release modulation, and ability to extend release of some cationic drugs. Recently, the Research Group at Colorcon has shown that a mixed matrix incorporating HPMC/Carbomer/polyvinyl acetate phthalate (PVAP) provided slower release than single or binary systems. This was ascribed to a synergistic increase in viscosity/gel strength, possibly due to stronger hydrogen bonding between the hydroxy groups of HPMC and the carboxylic functions of the carbomer or PVAP. Stronger bonding provided a more rigid structure for drug diffusion [91, 93]. The influence of combination of carbomer, PVAP, and HPMC blend in a matrix formulation of Guaifenesin, a soluble drug is shown in Fig. 7.1 [94].

15% METHOCEL -30% METHOCEL 15% Blend 30% Blend

Fig. 7.1 Drug release profile of Guaifenesin from matrices containing 69% drug, 15% or 30% METHOCEL™ K4M CR or combination of METHOCEL™ K4M CR+carbomer and polyvinyl acetate phthalate, qs % Fast-flo lactose and 0.5% w/w each of Cab-O-Sil and magnesium stearate. Dissolution study was performed using USP apparatus II at 100 rpm and 900 ml of deionized water

15% METHOCEL -30% METHOCEL 15% Blend 30% Blend

Fig. 7.1 Drug release profile of Guaifenesin from matrices containing 69% drug, 15% or 30% METHOCEL™ K4M CR or combination of METHOCEL™ K4M CR+carbomer and polyvinyl acetate phthalate, qs % Fast-flo lactose and 0.5% w/w each of Cab-O-Sil and magnesium stearate. Dissolution study was performed using USP apparatus II at 100 rpm and 900 ml of deionized water

A 15% inclusion level of the combined polymer provided a release profile similar to those exhibited with an inclusion level of 30% HPMC alone. Such a "polymer-sparing" effect can be beneficial where dose of drug is high, facilitating unit size reduction and cost savings.

The combined polymer matrix also engendered lower microenvironmental pH (3.5-4.5) within the gel layer (microenvironmental pH of HPMC alone matrix is 7.4-8.2). This may help improve solubility or possibly stability of some basic drugs. Moreover, the combination can produce matrices with higher gel strength that are less sensitivity to hydrodynamic conditions. Comparable dissolution profiles were evident at stirring rates of 50, 100, and 150 rpm in USP II Dissolution Apparatus [95]. Polyethylene Oxide

Polyethylene oxide (PEO) [POLYOXTM] resins are water soluble, nonionic polymers manufactured by Dow Chemical Company and distributed worldwide by Colorcon [96]. They are free flowing white powders, soluble in water at temperatures up to 98°C and in certain organic solvents. Structures comprise the repeating sequence -(CH2CH2O)n where n represents the average number of oxyethylene groups. It is highly crystalline and available in molecular weight grades ranging from 1 x 105 to 7 x 106 Da. Their high molecular weights mean that the concentration of reactive end groups is very low. However, as their paired ether-oxygen electrons have a strong affinity for hydrogen bonding, they can form association complexes with a variety of monomeric and polymeric electron acceptors (e.g., gelatin, carbomer) as well as certain inorganic electrolytes, e.g., alkali halides [97].

PEO resins are among the fastest hydrating water soluble polymers, quickly forming hydrogels that initiate and regulate drug release. Systems using such resins are often superior in approaching zero-order release profiles. PEO can be used at 20-90% inclusion level depending on the drug and the desired release characteristics.

PEO behaves similarly to HPMC in hydrophilic matrix systems. With appropriate selection of a suitable viscosity grade, one may be able to achieve release profiles similar to hypromellose matrices [98]. Grades available are POLYOX WSR-205 NF, WSR-1105 NF, WSR N-12 K NF, WSR N-60 K NF, WSR-301 NF, WSR-303 NF, and WSR Coagulant NF. The high swelling capacity of PEO has been used in hydrophilic matrices to achieve expanded swelling, providing enhanced gastrore-tention. A formulation of gabapentin containing PEO and HPMC exhibited significant matrix swelling and gastric retention [99].

PEO can undergo chain cleavage via auto-oxidation leading to loss of viscosity in aqueous solution. Higher molecular weight grades are more sensitive to such oxidation. Rate of auto-oxidation can be minimized by including antioxidants and by controlling storage conditions. Commercially available PEO grades are supplied with the added antioxidant, usually butylated hydroxytoluene (BHT) at inclusion levels of 100-1,000 ppm, depending on the molecular weight of the polymer.

Inclusion of lactose, a reducing sugar, or mannitol, a reducible organic compound, as excipients in PEO matrices can cause instability of the PEO [100]. Destabilization has been attributed to the relative ease of aerobic auto-oxidation in the presence of these excipients, generating active oxygen species leading to het-erolytic depolymerization of high molecular weight PEO, viscosity reduction, and faster drug release.

Poly (ethylene oxide) resins have melting points ranging from 63 to 67°C, becoming thermoplastic. Hence, they are suitable for hot melt extrusion, injection molding, or calendaring processes [98, 101-103] and discussed in a separate chapter in this book.

Several other materials can be useful gel matrix formers. They include methyl-cellulose [104], guar gum [105], chitosan [106], and cross-linked high amylose starch [107]. They are not widely used but, on occasion may be imminently suited for a specific drug, for delivery of a defined mode of release and absorption.

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