Cellulose is the main structural component of cell walls in higher plants and consists in linear, unbranched polysaccharide of β-1,4-linked d-glucose units. Cellulose chains form long crystalline microfibrils aligned with each other’s to provide structural support to the cell wall [7]. The strong structure of cellulose provides a high resistance against enzymatic reactions that degrade the chains. It is also insoluble in water and indigestible by the human gastrointestinal system. Modifications of cellulose structure leads to materials widely used in the pharmaceutical field to facilitate the manufacture of drugs:

Starch is a storage carbohydrate consisting of glucose monomers organized as amylose and amylopectin chains. Starches are used in solid oral formulations as diluents, binders and disintegrants. Deficient flow properties of natural starches can be overcome by substitution with acetate groups, prepared by partial reaction of the hydroxyl groups of starch with acetic acid anhydride in an acetyl esterification reaction [8, 11]. Alternatively, flow properties can be improved via chemical and/or mechanical processing to break all or part of the starch granules (namely, the bonds between amylose and amylopectin molecules) in a process named pregelatinization. Partial pregelatinization renders the starch flowable, directly compressible, and suitable for preparing oral capsules. Both partial and fully pregelatinized can be used in wet granulation processes. Combination of pregelatinized starch with amylose and amylopectine leads to multifunctional excipients that are effective as binders, disintegrants, flow aids and lubricants [12]. Most known commercial brands are Starch 1500^®, Sepistab ST200^® and C*PharmGel^®.

Anionic polysaccharides extracted from seaweeds (alginate, agar, carrageenans; Fig. 11.3) and plant cell walls (pectin) and exudates (gum arabic) are largely used as thickening and gelling agents. Alginate is a linear polysaccharide composed of β(1-4)-d-mannosyluronic acid (M) and α(1-4)-l-gulosyluronic acid (G) blocks. The ratio and the distribution of the M and G blocks (Fig. 11.3) notably affect to the sensitiveness of alginate to pH and calcium ions because the different relative position of the carboxylic acid group in each block [13]. Alginate also offers a wide range of possibilities of derivatization to improve its performance [14]. Alginic acid and its sodium, calcium, ammonium and potassium salts have been shown suitable for oral and topical dosage forms, acting as diluent and disintegrant in solid forms and as thickener, emulsifier and taste-masking agent in liquid and semisolid. Alginic acid is particularly suitable for preparing microcapsules, pellets and microspheres that are easily cross-linked in the presence of calcium ions [15].

Carrageenans or carrageenins are hydrocolloids extracted from some red seaweeds. They mainly consists of linear β-d-galactose and 3,6-anhydro-α-d-galactose copolymers with a variable density in sulfated groups, which leads to three different families: kappa (κ, 1 sulfate group per dimer) which has a helical tertiary structure and strong gelling capability; iota (ι, 2 sulfate groups per dimer); and lambda (λ, 3 sulfate groups per dimer) which does not form gels (Fig. 11.3). Only κ-carrageenan hydrogels exhibit pH- and temperature-sensitiveness [16]. At low concentration, carrageenans are added to emulsions to increase the physical stability. They are also used as pelletizer agents for extrusion-spheronization, binder agents in tableting, and as components of hard and soft capsule shells.

Agar or agar-agar is obtained from the cell walls of some species of red algae or seaweeds and is widely employed as emulsifying and suspending agent, thickener, and tablet binder. Agar is a heterogeneous mixture of two unbranched polysaccharides: agaropectin and agarose, which share the same galactose-based backbone (Fig. 11.3). Agaropectin is heavily modified with acidic side-groups, such as sulphate and pyruvate, while agarose has neutral charge and possesses longer chains [17]. Thus, depending on the composition, agar are designed as neutral agarose, pyruvated agarose (with little sulfation) and sulfated galactan.

Polyvinylpyrrolidone (PVP), also known as povidone and commercialized as Kollidon^® (Fig. 11.4), is a synthetic linear polymer widely used in pharmaceutical industry. It is highly soluble in water, but also in some organic solvents such as butanol. The thickening ability of PVP depends on its molecular weight, and several grades can be distinguished which are identified with a K-value (average molecular weight estimated from relative viscosity values). PVP is also used as adhesive and binding agent in tablets, and as taste masker in oral solutions and chewing tablets. Chemically and physically cross-linked insoluble PVP (crospovidone) has good flow properties and strong swelling capability, performing as disintegrant of tablets. Water-soluble copolymers of N-vinylpyrrolidone and vinylacetate (copovidone; Fig. 11.4) are used as binders and as film-forming agents of tablets, pellets and granules. Compared to PVP grades, copovidone has lower hygroscopicity, better dry binding properties, and higher plasticity [18].

High molecular weight, crosslinked, acrylic acid-based polymers are known as Carbopol^® and Noveon^®. Carbopol^® homopolymers consists of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol. There exist also Carbopol^® copolymers (with C10-C30 alkyl acrylate) and interpolymers (which contain a block copolymer of polyethylene glycol and a long chain alkyl acid ester). Noveon^® polycarbophil is a polymer of acrylic acid crosslinked with divinyl glycol [19].

These polymers have microgel structure and behave as thickening agents in lotions, creams and gels, oral suspensions, and in transdermal gel reservoirs. They are also useful to communicate controlled release properties to solid dosage forms. In contact with the aqueous media, acrylic acid-based polymers form gel matrices that hinder drug diffusion more efficiently than other polymers. It should be noticed that due to the presence of carboxylic acid groups, acrylic acid-based polymers undergo relevant conformational changes as a function of pH and ionic strength. At pH above the pKa (5.5–6.5), the ionized polymer chains expand and can easily entangle with neighbor chains forming highly structured, viscoelastic gels.

Polyesters are biocompatible and biodegradable polymers including poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly-ε-caprolactone (PCL). These biocompatible polymers are widely used to encapsulate drugs in micro/nanoparticles and in macroscopic implants [20, 21]. Poly(α-hydroxy) esters are not biodegraded by enzymes in the body, but undergo hydrolytic degradation via surface or bulk degradation pathways. Surface degradation occurs when the rate of hydrolytic chain scission and the production of oligomers and monomers which diffuse into the surroundings is faster than the rate of water intrusion into the polymer bulk. As a consequence, the formulation erodes over time without affecting the molecular weight of the polymer bulk. Bulk degradation occurs when water penetrates the entire polymer structure, causing hydrolysis throughout the entire polymer matrix and thus overall reduction in molecular weight. In the case of PLGA, if the generated carboxyl-containing species do not diffuse out the matrix, they can act as internal autocatalyzer that accelerates the bulk degradation compared to the surface. Due to these biodegradation patterns, PLGA formulations exhibit bi/triphasic release profiles: initial burst of drug close to the surface, slow release of the entrapped drug until the molecular weight of the polymer becomes lower than a critical threshold, and rapid release when most polymer has degraded [22]. PCL is less used mainly because it bioerodes at slower rate than other aliphatic polyesters, but has the advantage of degrading in neutral species and not in acid byproducts [23].