Inert Matrices

Table 7.4 lists water insoluble and lipidic materials commonly used for fabrication of inert matrices, along with their FDA listed maximum use level in designing oral formulations [34].

7.4.2.1 Ethylcellulose

Ethylcellulose is prepared by reacting alkali cellulose with ethyl chloride: It is characterized by degree of ethoxy substitution and associated molecular weight and is available in different molecular weights with varying viscosities in organic solvents. Multiple particle size grades are also available. It is manufactured by The Dow Chemical Company and commercially available as a dry powder (ETHOCEL™) or as an aqueous dispersion (Surelease®) from Colorcon.

Standard and fine particle size grades have been evaluated for manufacturing ER matrices by DC [108-110]. Utility as a sole matrix former in the dry state at high concentrations may, however, be limited by poor flow and static charge. Aqueous dispersions (Surelease) or in organic solution (ETHOCEL) have been used as wet granulation agents in ER inert matrix formulations [111]. Release profiles of theophylline from Surelease-granulated inert matrices are shown in Fig. 7.2a, b.

Tablets containing lactose as filler showed minimum influence of compression force on release profile. However, tablets containing microcrystalline cellulose had slower release rates at higher compression forces, to a threshold of 15-20 kN. The effects were attributed to the nature of these excipients, with mode and extent of deformation during compression affecting tablet porosity. Tablets containing lactose remained intact during dissolution while those containing microcrystalline

Table 7.4 FDA registered oral formulations containing commonly used water-insoluble polymers'

materials [34]

Table 7.4 FDA registered oral formulations containing commonly used water-insoluble polymers'

materials [34]

No of hits on FDA

Maximum potency listed

Polymer/material

Web pagea

for oral formulations (mg)b

Water-insoluble polymers

Ethylcellulose

19

308.80

Cellulose acetate

10

47.49

Cellulose acetate phthalate

7

70.00

(CELLACEFATE)

Methycrylic acid copolymers

50

430.80c

Poly(vinyl acetate)

2

46.00

Zein

4

135.00

Shellac

11

87.00

Fatty acids/alcohols/waxes

Bees wax

8

16.80

Carnauba wax

22

300.00

Paraffin wax

5

150.20

Cetyl alcohol

5

59.00

Cetosterayl alcohol

2

70.00

Stearyl alcohol

4

244.00

Glyceryl behenate

10

50.60

Glyceryl monosterate

12

264.30

Hydrogenated vegetable oil

11

261.00

Hydrogenated cottonseed oil

7

402.00

Hydrogenated castor oil

11

410.82

Hydrogenated soybean oil

5

15.30

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 for enteric product 430.8

cellulose split. This effect was attributed to the capillary effect of microcrystalline cellulose facilitating migration of dissolution media into the inert matrix resulting in crack formation, splitting, and faster drug release. This example illustrates how type of filler may affect compact properties such as mechanical strength, porosity, and tortuosity and as a consequence drug release.

Ethylcellulose is thermoplastic, with a glass transition temperature of 120°C, making it suitable for melt extrusion as discussed in a separate chapter.

7.4.2.2 Polymethacrylates

Polymethacrylates (Eudragits®, Evonik) are synthetic cationic or anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several types are commercially available as dry powders, aqueous

Time (hours)

Time (hours)

Fig. 7.2 Drug release profile of theophylline from Surelease granulated inert matrices. (a) Lactose as filler. (b) Microcrystalline cellulose as filler. Formulations consisted of 44% drug, 11% Surelease (on dry basis), 44% filler (lactose or microcrystalline cellulose), and 0.5% each of silicon dioxide and magnesium stearate. Studies utilized USP Apparatus II with sinkers, stirring at 100 rpm and 1,000 ml of DI water at 37 ± 0.5°C

Time (hours)

Fig. 7.2 Drug release profile of theophylline from Surelease granulated inert matrices. (a) Lactose as filler. (b) Microcrystalline cellulose as filler. Formulations consisted of 44% drug, 11% Surelease (on dry basis), 44% filler (lactose or microcrystalline cellulose), and 0.5% each of silicon dioxide and magnesium stearate. Studies utilized USP Apparatus II with sinkers, stirring at 100 rpm and 1,000 ml of DI water at 37 ± 0.5°C

dispersions, or organic solutions. Polymethacrylates can be used as binders for both aqueous and organic solvent granulation, forming matrices with ER characteristics. In general, greater polymer inclusion levels (5-20%) are used to control release from matrices but inclusion levels of 10-50% may be required in direct-compression operations [112, 113]. Interactions between polymethacrylates and some drugs can occur depending on their ionic and physical properties. Drug release may also be affected by pH of the dissolution medium.

7.4.2.3 Polyvinyl Acetate

Polyvinyl acetate (PVAc) is a synthetic polymer, prepared by polymerization of vinyl acetate monomer. PVAc-based matrix formulations provide strong sustained release functionality.

PVAc is available in two different forms from BASF [114], viz.:

• Kollidon® SR, which consists of a physical mixture comprising 80% PVAc and 20% povidone (PVP K30).

• Kollicoat® SR 30 D, which is a PVAc aqueous dispersion stabilized with povi-done and sodium lauryl sulfate.

Kollidon SR provides a coherent matrix even under low compression forces. When tablets are introduced into gastric or intestinal fluid, the water-soluble povi-done component leaches out, leaving pores through which the active ingredient diffuses. The good flow and compressibility of Kollidon SR renders it suitable for DC tableting processes but matrices can also be prepared using wet granulation or melt extrusion: Suitability in the latter case is attributable to the thermoplastic nature of the PVAc. Inclusion level may depend on active ingredient solubility, varying from 15% for poorly soluble drugs to 55% for soluble actives [115].

Drug release from Kollidon SR matrices is independent of compression force. Aqueous dispersions of Kollicoat SR 30 D can be used as a release retarding binder in wet granulation processes. Depending on the solubility of the active ingredient and the required dissolution profile one may need to add pore former or channeling agent to modulate release rate.

PVAc is used in a commercially available ER matrix tablet [116].

7.4.2.4 Cellulose Acetate and Cellulose Acetate Butyrate

Cellulose acetate consists of cellulose with a portion or all of the hydroxyl groups acetylated. It is available commercially from Eastman Chemicals in a wide range of acetyl levels, chain lengths, and molecular weights that have varying properties [117]. They have been extensively used in the development of osmotic delivery systems, mainly as semipermeable coatings. ER inert matrix tablets can also be formulated with cellulose acetate as a directly compressible matrix former [118]. Release profile can be modified by changing the ratio of drug to cellulose acetate and incorporation of a plasticizer.

Cellulose acetate butyrate (CAB) has also been used as an inert matrix former. Drug release profiles from CAB matrices were reported to be slower than from CA matrices.

7.4.2.5 Fatty Acids, Alcohols, and Waxes

Fatty acids, alcohols, and waxes that do not melt at body temperature are used as insoluble matrix formers. Examples include hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, stearic acid, cetyl alcohol, cetostearyl alcohol, and carnauba wax [55, 119, 120]. As these materials are insoluble in water, drug release from their matrices is mainly diffusional in nature. The presence of channeling (wetting) agents in the matrix can modulate drug release.

These hydrophobic materials are derived from natural products and tend to be complex multicomponent mixtures [119]. Hence, source or changes in isolation and purification may change composition in subtle ways, and consequently influence release profiles. Fatty acids and waxes exhibit complex solid state behavior, including polymorphism. Phase transition behavior may change cooling rate during processing and affect release rate. Waxes may also coat the drug particle during processing such that complete release is prevented. Moreover, low melting waxes (melting point <50°C) can cause sticking and picking during tableting [121, 122]. Digestion during GI transit could also affect release.

Matrices containing these materials can be formulated by DC or more commonly by fusion, drug and additive being mixed with the molten wax matrix at a temperature slightly above the melting point. The molten mass is then spray congealed, solidified, and milled to form granules for compression to tablets [1].

Some other materials may be useful matrix formers. These include zein [123], shellac [124], and cellulose acetate phthalate [125]. Enteric polymers such as HPMC acetate succinate have also been reported [126] but are not widely used.

In summary a dosage form needs to be designed to release drug in a mode or rate that delivers the requisite target drug plasma profile. In hydrophilic matrices, strategies to regulate gel strength, hydration rate, and pore formation in matrices can all be used, separately or in concert to achieve such delivery. Dissolution from gel forming or insoluble matrices generally is influenced by:

• Reducing gel strength to increase erosion rate and/or drug diffusivity in a hydro-philic matrix. This may be achieved by using lower viscosity polymers.

• Reducing hydration rate can mean less complete gel formation and faster release.

• Pore formation by incorporating additives with greater solubilities or by adding a greater percentage of pore forming materials.

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