Recent advances of starch-based excipients used in extended-release tablets: a review

Abstract

In recent years, polysaccharides, including starch and its derivatives, have been widely used in the pharmaceutical industry, including as diluents, fillers, binders, disintegrants and glidants. The use of native starch as excipient in extended-release tablets is limited due to its low compactibility and enzymatic degradability, leading to the formation of weakly structured tablets. To overcome these limitations and expand the application of starch as an excipient, researchers have modified starch by physical and chemical methods, as well as by enzymatic hydrolysis. Some starch derivatives, including retrograded starch, pregelatinized starch, carboxymethyl starch, starch acetate, cross-linked starch and grafted starch have recently been introduced as excipients in oral tablets to control drug release. In this review, applications of starch and its derivatives as extended release excipients are reviewed and future frontiers are described.

• Excipient
• extended release
• matrix
• starch derivative
• tablet

Introduction

In recent years, modified starches have been extensively used in pharmaceutical companies worldwide in different stages of drug development. Excipient dominates in solid dosage formulation by rendering mechanical strength, stability and tablet disintegration.

Native starches, as natural and secure excipients, have been used as classic tablet disintegrants, fillers and binders. However, they suffer from low compactibility and elastic compression behaviors. Meanwhile, orally administered drugs comprising native starches are subject to being eroded by α-amylase in the gastrointestinal tract and thus fail to extend the drug release (Prado et al., 2009). Therefore, natural starches should be modified by physical and chemical methods, as well as by enzymatic hydrolysis, in order to overcome these limitations and expand the application of starch as an excipient.

During the past two decades, numerous studies have prepared oral extended release tablets by starch and its derivatives. Many starch-based extended release excipients have successfully retarded drug releases. This review aims to summarize the recent development of starch-based excipients used in matrix tablets and to be aware of the extended release delivery systems relating to controlled release.

Retrograded starch

During the retrogradation of starch, the chains re-associate through intramolecular hydrogen bonding and intermolecular van der Waals forces. Meanwhile, starch paste is recrystallized, thus raising the enzymatic resistance (Tako et al., 1996), the amount and polymorph of which are relevant to the retrogradation conditions such as temperature and retrogradation rate. Commonly, the polymorph of retrograded starch contains more B-type crystals characterized by double helices (Marsh & Blanshard, 1988), and adding water can mobilize the starch chains. Starch is optimally retrograded and recrystallized at 4 °C and 50%–60% of water content. Furthermore, mild heating during refrigeration facilitates the growth of starch crystals (Yoon et al., 2009), and temperature cycling elevates the pasting temperature and viscosity of retrograded starches compared with isothermal storage does. Thus, retrogradation increases the content of slowly digested starch without altering that of resistant starch, which becomes more prominent by temperature cycling rather than isothermal storage (Zhou & Lim, 2012). Besides starch crystals, amorphous starch, which plays an essential role in the formation of gel network structure, also dominates in the drug release from extended release tablets. The amorphous and non-ordered starch chains develop into a non-ordered gel network after association, which highly resists to the erosion of gastrointestinal enzymes and benefits the controlled release of drugs from tablet matrix.

The effects of retrogradation on the drug release from retrograded starch-based tablets were further investigated by Yoon’s research group (Yoon et al., 2009). They prepared theophylline tablets by waxy maize starch gels and investigated the effect of retrogradation on the release of theophylline. They found that both the air cell sizes and the gel pore sizes decreased by increasing the duration of 4 °C-retrogradation. Moreover, the cell walls were attenuated. The retrogradation-induced results enhanced the resistance to enzymatic erosion and decreased the ability of swelling in aqueous matrix. They also found that the temperature-cycled retrogradation under 4/30 °C cycles yielded a more compact matrix structure with lower swelling ability, which is the premise of resisting to enzymatic hydrolysis. Therefore, the temperature-cycled retrogradation effectively extended the release of theophylline by forming a stable amorphous network.

Enzymatically modified starch

The molecular weight distributions of starch macromolecules together with the chain lengths of enzymatically modified starches affect the properties of starches such as viscosity and texture, which also reveal the enzymatic processes beneath starch synthesis (Castro et al., 2005). Pullulanase and isoamylase enzymatically hydrolyze the α-1,6 glycosidic bonds of amylopectin selectively. The digestibility of debranched products is related to the molecular and crystal structures as well as morphology during the debranching and crystallization of native starches (Cai et al., 2010; Cai & Shi, 2010). Linear short chain amylose (amylodextrin) is produced due to debranching enzyme, followed by precipitation, filtration and ethanol washing. The enzymatically modified starch extended the release of drugs at an almost constant rate. Moreover, this product is featured in the high-specific surface area owing to ethanol washing, which augmented the compactibility of starch products following an almost zero-order sustained drug release (Wierik et al., 1997a,b).

The tablets containing the new linear short-chain starch product did not disintegrate and functioned following an almost constant sustained drug release. During swelling, a solvent front slowly penetrated into the tablets, and the delivery from these tablets followed a swelling-controlled solvent-activated mechanism. The incorporation of magnesium stearate into the tablets or α-amylase in the dissolution medium did not influence drug release. Tablets containing the starch with a lower specific surface area show an increased and less constant release rate and higher standard deviations. When the specific surface area is lower than 1.0 m²/g, the tablets will rapidly disintegrate and show a faster drug release. A specific surface area of 1.5 m²/g is required in order to obtain a zero-order release (Wierik et al., 1997a,b).

Our research group recently investigated the extended-release properties of amorphous debranched starch (ADBS) derived from pullulanase enzymatic modification (Liu et al., 2013). The results showed the enzymatically modified starch-based tablets could effectively retard drug release for more than 12 h. Different factors (e.g. pH, pancreatin and ionic strength) of dissolution medium for ADBS-based tablets were evaluated. We found the drug release, which was accelerated by decreased pH and pancreatin, was barely affected by ionic strength. The drug release data were best fitted to the Higuchi equation, and the drug release process was dominated by Fickian diffusion. We confirm ADBS is able to be used in oral tablets to extend drug release.

Substituted starches

Substituted starches are prepared by esterifying and etherifying the hydroxyl groups of glucose units, such as acetylated starch (Ali & Hasnain, 2011; Han et al., 2012), carboxymethyl starch (CMS) (Tatongjai & Lumdubwong, 2010; Bhandari & Hanna, 2011), hydroxyethyl starch (Liu et al., 2003), hydroxypropylated starch (Chuenkamol et al., 2007) and phosphate starch (Park et al., 2004). The substituted starches are prepared in aqueous, organic or water-miscible organic media. Organic media allow higher substitution, but residues such as by-products and salts remain in the finial products (Assaad & Mateescu, 2010).

Carboxymethyl starch

CMS is a pH-sensitive tablet excipient that modulates drug release according to the physiological pH values. Until now, high amylose starch (more than 70% amylose) has been used as the reaction substrate in most cases of CMS preparation. An oral dosage form can be readily prepared by dry-mixing and directly compressing drugs and CMS.

The carboxyl groups of starches are dimerized by hydrogen bonds in acid fluids, and the resultant dimerization and hydrogen bonds enhance the stability of tablets. When the CMS tablets were transferred into a high pH fluid (SIF, pH 6.8), protons started to exchange with cations between the matrix and aqueous medium. This hydration facilitated the swelling, diffusion and erosion of the matrix, as well as the release of bioactive agents (Assaad et al., 2011). CMS is lately added to tablets as a pH-sensitive excipient to protect bioactive agents from being destructed by strong acidic gastric fluids. The properties of CMS excipients and the drug release mechanisms concerning monolithic tablets have been frequently referred. Numerous researchers have investigated the influences of the percentage of protonation, the degree of substitution (DS) (Figure 1) and amylose content on the release kinetics of small bioactive agents from CMS matrix tablets (Table 1) (Lemieux et al., 2009; Tatongjai & Lumdubwong, 2010; Assaad et al., 2011).

Figure 1. Physical appearance of CMS- (high amylose content) based tablets with different DS incubated in SGF for different time (Lemieux et al., 2009). (A): High amylose starch (HAS) without carboxymethylation (DS 0); (B): CMS with a DS of 0.09 (DS 0.09); and (C): CMS with a DS of 1.23 (DS 1.23). Reprinted from International Journal of Pharmaceutics, Vol. 382, Lemieux M, Gosselin P, Mateescu MA, Carboxymethyl high amylose starch as excipient for controlled drug release: mechanistic study and the influence of degree of substitution, pp. 172–182, Copyright (2009), with permission from Elsevier.

Figure 2. SEM micrographs of radial cross-sections of SA based tablets (Pohja et al., 2004). (A) Tablet containing 80% SA (DS 3.0) before the dissolution test. Voids formed after the densification process indicate the incorporation of drug model decreased the compactibility of tablets; (B) tablet containing 84% SA (DS 2.6) after the dissolution test. The drug was released completely, and some pores were formed during drug dissolution (shown by the white arrows.); (C) tablet containing 80% SA (DS 3.0) after the dissolution test. A distinct solvent front formed in the tablet, and the drug in the core of the tablet was not dissolved; (D) tablet containing 75% SA (DS 2.6) after the dissolution test. The white arrows indicate macroscopic cracks formed on the horizontal plane in the middle of the tablets when the SA concentration was lower than a certain degree. Reprinted from Journal of Controlled Release, Vol. 94, Pohja S, Suihko E, Vidgren M, Paronen P, Ketolainen J, Starch acetate as a tablet matrix for sustained drug release, pp. 293–302, Copyright (2004), with permission from Elsevier.

Table 1. Investigations of carboxymethyl starch used in extended-release matrix tablets.

Influence factors	Summary	References
Amylose content	1. Cold water solubility increases when amylose content increases. 2. Yield stresses and apparent viscosities of CMS samples decrease with increased amylose content. 3. DS plays a more important role than amylose content in determining the physicochemical and functional properties of CMS.	(Tatongjai & Lumdubwong, 2010)
Geometries of tablets	1. The release time of the larger CMS tablets is longer. 2. The effect of DS and PR on release profiles for tablets with different sizes is similar.	(Assaad & Mateescu, 2010)
Electrolyte (NaCl)	1. Adding an optimized quantity of sodium chloride pumps more water into the tablets faster. The existence of NaCl provides the tablet with improved integrity for oral administration.	(Nabais et al., 2007)
Protonation ratio (PR)	1. The protonated CMS shows a lower solubility and a more progressive structural alteration. 2. Release time is prolonged by increasing PR. 3. The protonated form of CMS better resists to the erosion of gastric acid.	(Assaad & Mateescu, 2010)
DS	1. In SGF, an increase of DS leads to an acceleration of release rate (Figure 1). A low substitution (DS 0.07) generates the longest release time (about 11 h). In SIF, the CMS (DS 0.11) shows the longest release time compared with DS (0.07) and DS (0.20). 2. The CMS (DS 2.0) tablets with PR up to 50% are sensitive to the pH of dissolution medium, whereas those with 0.11 of DS are less sensitive. 3. Increasing DS results in an increasing enzymatic resistance. 4. CMS (DS 0.1–0.2) can be used as sustained release excipient; while CMS with high DS (0.9–1.2) can be used as delayed release excipient.	(Assaad & Mateescu, 2010) (Kwon et al., 1997) (Lemieux et al., 2009)
Dissolution medium	1. The drug release is longer in SGF (pH 1.2) than in SIF (pH 6.8). 2. The change for CMS tablets with PR is less pronounced in SGF than in SIF. 3. The drugs in CMS tablets are released following a diffusion mechanism in SGF. However, the release in SIF is cooperatively controlled by swelling and erosion. 4. The enzymatic resistance of Pancreatin is controlled by the combination of DS and the hydrated gel-layer.	(Assaad & Mateescu, 2010) (Lemieux et al., 2009)
Storage time	1. The solubility of CMS is decreased with the prolonged storage time. 2. Acceleration of the drug release is observed in function of CMS samples storage time. 3. An increase of carboxyl- carboxyl and carboxyl-hydroxyl interaction can be obtained over storage time.	(Assaad & Mateescu, 2010)

Starch acetate

Starch acetate (SA) is a film-forming polymer produced by acetylating native starch (Tarvainen et al., 2002). Unlike other modified starches, SA is less hydrophilic due to the hydrophobic nature of acetoxy substituent (Pohja et al., 2004).

Highly substituted SA has been introduced for directly compressed tablets as a pharmaceutical excipient (Korhonen et al., 2004). Highly substituted SA (DS 2–3) is soluble in acetone, chloroform and other organic solvents. Moreover, the thermoplastic property of high acetyl-substituted starch and the above properties are in need of an in-depth study (Singh et al., 2011). The acetylation of native starch considerably overcomes the substantial swelling and rapid enzymatic degradation in biological fluids, which can be ascribed to the raised hydrophobicity and steric bulkiness of the modified starch owing to the acetyl groups of SA (Tuovinen et al., 2003).

Drugs are released from the SA matrix monolithic tablets via diffusion in most cases. Many factors, such as SA properties, the porosity and compaction of tablets, the concentration ratio of drug to SA in the formulation, the physicochemical nature of drugs, remarkably affect the drug release behaviors. The drug release profile is governed by taking all the above variables into consideration (Table 2) (Korhonen et al., 2004).

Table 2. Evaluations of starch acetate used as an excipient.

Influence factors	Summary	References
Drug type	1. The drug release rate decreases in correspondence to the increase in molecular weight of the drug. 2. The hydrophilic drugs are released faster than the more lipophilic drugs.	(Tuovinen et al., 2003)
DS	1. Drug release rate is negatively correlated with the contents of DS (Figure 2B and C).	(Tuovinen et al., 2003)
	2. The SA powder with 3.0 DS is prone to being compacted than that with 2.6 DS.	(Pohja et al., 2004)
SA concentration	1. The compactibility of SA powders is lowered with decreasing SA concentration (Figure 2A). 2. A decrease in SA concentration increases the drug release rate.	(Pohja et al., 2004)
Cracks	1. During dissolution tests, the tablets are macroscopically cracked on the central horizontal plane, which enlarge the available areas for Fickian diffusion, thereby decelerating the drug release (Figure 2D).	(Pohja et al., 2004)

Cross-linked starch

Cross-linked high amylose starch (CLHAS) was introduced in the early 1990s as a tablet excipient for drug controlled release with the brand name Contramid® (Lenaerts et al., 1991, 1998; Dumoulin et al., 1998). CLHAS is generally derived from the cross-linking of high amylose starch (70% amylose, 30% amylopectin) with epichlorohydrin or phosphate (Rahmouni et al., 2001). CLHAS tablets are of high drug loading and quasi zero-order release profiles. Compared to other excipients, CLHAS is more suitable for hydrophilic matrices preparation. The water uptake rate, drug release rate and equilibrium swelling are elevated with increasing cross-linking degree (cld), which is ascribed to the unique characteristics of CLHAS tablets, such as erosion resistance and swelling restriction (Lenaerts et al., 1998).

CLHAS tablets swell in aqueous medium, yielding an elastic gel layer on the surface of tablets (Ispas-Szabo et al., 2000). Hydrogel, which functions superbly as a pharmaceutical excipient due to the appropriate swelling resistance and drug release control, forms a gel network upon drug captures and thus hinders the release to the surrounding medium (Onofre et al., 2009). Cross-linked amylose (CLA) with low cld shows intriguing mechanical and sustained release properties. Unlike other polymeric matrices, CLA tablets can no longer control drug release with increasing cld. High-cld CLA excipient outweighs others as a binder or disintegrant (Dumoulin et al., 1998), which is closely related to the network organization. The result is consistent with the hypothesis that network organization and water availability dominate in drug release kinetics. The matrix cohesion and sustained release properties of tablets are determined by covalent linkages and inter-chain hydrogen bonds (Figure 3). Particularly structured low-cld CLHAS matrix is conducive to controlling the release behaviors. The crystal morphology of low-cld CLHAS is transformed from B-type double helix to V-type single helix, leading to the intriguing dissolution kinetics and mechanical hardness of dry tablets (Ispas-Szabo et al., 2000). Nevertheless, the network organization of high-cld CLHAS entraps more water molecules, which promotes the swelling of tablets and accelerates the release of drugs. The investigations were exhaustively described in Table 3.

Figure 3. Schematic representation of the covalent and hydrogen bonding stabilization of CLA (Dumoulin et al., 1998). (A) CLA with low-moderate cld and (B) CLA with high cld. Reprinted from Carbohydrate Polymers, Vol. 37, Y. Dumoulin, Alex S, Szabo P, Cross-linked amylose as matrix for drug controlled release. X-ray and FT-IR structural analysis, pp. 361–370, Copyright (1998), with permission from Elsevier.

Table 3. Investigations of cross-linked starch used in extended-release matrix tablets.

Cross-linking agents	Summary	References
Crystalline/amorphous structure	1. The B-type double helix will be transformed to the V-type single helix and more amorphous conformations by increasing cld.	(Dumoulin et al., 1998)
	2. In the gel state, the V-type single helix in the CLHAS tablets is transformed to the B-type double helix with low cld.	(Rahmouni et al., 2001)
	3. A gel layer can rapidly form on the surface of the tablets. The gel front diffuses into the tablets and reaches the center in about 30 min. During drug release, a membrane and solvent front form in the swelling tablet (Figure 4E). An X-shape cavity in the internal texture is evident after the dissolution test (Figure 4D).	(Lenaerts et al., 1998)
Cross-link degree (cld)	1. The chains of low-cld CLA are closely located and stabilized by hydrogen bonding. Thus, the resulting tablets contain low free water content, which resist to hydration and control drug release better (Figure 4A). 2. Increasing cld moderately shortens the drug release duration sharply from 20–24 h to 2–6 h (Figure 4B, 4C). 3. High-cld CLHAS is inert to the transition, which will account for the faster and easier water absorption and drug release utilizing high-cld polymers than those utilizing low-cld formulations.	(Dumoulin et al., 1998) (Rahmouni et al., 2001)
Others	1. The pilot clinical studies confirm that the extended-release properties of CHLAS matrices tablets are not influenced by tablet geometry, compaction pressure and diet. 2. Drug release kinetics appears to be relatively independent of pH, ionic strength and compression force. 3. In corporation of gel-forming polymers into the tablets results in a significance decrease of drug release rate. 4. The hydrolysis rate is closely related to the α-amylase concentration during the initial 2–4 h became independent in the second phase.	(Rahmouni et al., 2001)

Grafted starch

Modifying natural polymers chemically by grafting has attracted considerable attraction due to the integrated advantages of natural and synthetic polymers (Ochubiojo & Rodrigues, 2012). Modifying a host polymer by the graft copolymerization of guest monomers, such as ethyl methacrylate (Marinich et al., 2009, 2012), acrylamide (Singh & Nath, 2012a), methacrylic acid (Silva et al., 2011) and acrylic acid (Geresh et al., 2004; Eid, 2008), brings about innovative and desirable properties. In recent years, starch-based graft copolymers are of great significance in designing controlled release systems. Several researchers have investigated the influence of different factors on drug release of grafted starch-based tablets (Table 4).

Table 4. Investigations of grafted starch used in extended-release matrix tablets.

Influence factors	Summary	References
Graft copolymerization	1. Graft copolymerization will enlarge the particle size and decrease the density and moisture content. 2. Grafted starch is more amorphous than the raw tapioca starch. 3. The more irregularly shaped grafted starch particles require lower processing pressure. 4. The drying methods also significantly impact the copolymers. The products oven-dried (OD) in vacuum exhibited lower plasticity and higher elasticity than the freeze-dried (FD) copolymers.	(Casas et al., 2009)
Drug type	1. The drug with higher solubility and higher friability is in accordance with the faster drug release.	(Marinich et al., 2012)
EMA/starch ratios	1. The starch particles are surrounded by a grafting chain-derived acrylic layer, which effectively prevent the erosion of enzymes, and resulting more hydrophobic material prevented water from penetrating into the chain space. 2. Diverse EMA/starch ratios lead to small differences in the release profiles and the rates of enzymatic hydrolysis.	(Alias et al., 2007)

Graft copolymerization offers novel and eligible properties (Fares et al., 2003), during which 3D gel network structures are produced due to the participation of hydrophilic or hydrophobic groups in the guest monomer (Qiu & Park, 2001). Starch-based grafted copolymers are rapidly released from corresponding matrix tablets with high equilibrium swelling coefficients. Graft copolymerization primarily takes place in the amorphous regions of starch chains, generating numerous diffusion paths inside the copolymer through which drugs are able to permeate. Hence, the grafted starch is highly swollen in water (Al-Karawi & Al-Daraji, 2010). Meanwhile, grafted starch, which is a hydrophilic matrix, swells in aqueous media and is appropriate for preparing oral extended release dosage forms (Singh & Nath, 2012b).

Conclusions

Starches have been subjected to physical (retrograded starch) or chemical modification (cross-linked starch (CLS), SA, CMS and grafted starch) and enzymatic hydrolysis (linear short chain amylose) to control drug release as the excipients. A detailed comparison and contrast of different starch derivatives used as extended-release tablets excipients was presented (Table 5).

Table 5. Comparison and contrast of different starch derivatives used as extended-release tablets excipients.

Modified starch	Major influence factors	References	Tablets structural features	References	Drug release characterizations	References
Retrograded starch	Crystalline/Amorphous structure; temperature.	(Yoon et al., 2009)	Denser gel; less swollen and more enzyme-resistant structure.	(Yoon et al., 2009)	A constant drug release for over 6 h.	(Yoon et al., 2009)
Debranched starch	Specific surface area; amylose/amylopectin content; additional excipients.	(Wierik et al., 1997b, Wierik et al., 1997a)	A slow penetration of a solvent front into the tablet; good compactibility.	(Wierik et al., 1997a)	An almost constant (zero-order) drug release; a swelling-controlled solvent-activated mechanism.	(Wierik et al., 1997a)
Carboxymethyl starch	Amylose content; protonation ratio (PR); degree of substitution (DS).	(Tatongjai & Lumdubwong, 2010, Assaad & Mateescu, 2010, Lemieux et al., 2009)	A pH sensitive hydrophilic matrix; lower pH inducing a fast swelling; stable gel-layer formed at the presence of Na^+ ion.	(Lemieux et al., 2009)	A sustained release property (DS 0.1–0.2); a delayed release property (DS 0.9–1.2).	(Lemieux et al., 2009)
Starch acetate	Degree of substitution (DS); SA concentration; drug type.	(Tuovinen et al., 2003, Pohja et al., 2004)	Less hydrophilic matrix; cracks formed on the central horizontal plane of the tablets.	(Pohja et al., 2004)	Fickian diffusion.	(Pohja et al., 2004)
Cross-linked starch	Cross-link degree (cld). Crystalline/amorphous structure	(Dumoulin et al., 1998)	A gel layer rapidly formed on the surface of the tablets.	(Lenaerts et al., 1998)	A quasi zero-order release.	(Lenaerts et al., 1998)
Grafted starch	Graft copolymerization; drug type.	(Casas et al., 2009, Marinich et al., 2012)	A grafting chain-derived acrylic layer led to enzymatic resistance and hydrophobic behavior.	(Alias et al., 2007)	Fickian diffusion is the principal mechanism in most formulations. To some drugs, the release is an anomalous transport.	(Casas et al., 2009; Marinich et al., 2012)

Influence factors, like crystalline/amorphous structure, amylose/amylopectin content, DS and drug loading, play important roles in drug release properties from modified starch-based tablets. For starch excipients, good gel-forming capability is essential to retard drug release from tablets matrix. Compared to the other starch derivatives, more cracks formed on the central horizontal plane of SA and enzymatic debranched starch-based tablets. Cracks on the surface of tablets can effectively maintain the drug release at a similar rate and improve the bioavailability of drugs. In summary, a proper modification to native starch is feasible to prepare hydrophilic materials used as tablets excipients. To these starch derivatives, both gel-forming ability and digestibility are prerequisites for extending drug release from tablets.

Present aspects and prospects

For chemically modified starches, like CLS, SA, CMS, as well as grafted starch, high amylose starch is essential to obtain a better extended drug release profile. However, common starch can be used as material during enzymatic modification. Compared to chemical reagents used in chemical modification, pullulanase, as well as isoamylase, is safer to human health. As a personal point of view, enzymatically modified starch as extended-release excipient in oral tablets has a good application prospect.

There are an increasing number of papers about starch-based excipients used in extended-release tablets published in different journals. For most researches, too much attention was paid on the physicochemical properties of excipients and drug release study. However, fewer papers focused on the internal properties of the matrix. Personally speaking, the properties of matrix are the most important aspect, while drug release and physicochemical properties are secondary. Drug release property depends on several factors, like drug loading, compact force and it can be completely changed during hydration.

With the development of technology, several high-tech instruments have been introduced into the study of internal properties of matrix during hydration. Zhu, X.’s research group innovatively used nuclear magnetic resonance imaging in the study of internal properties of hydrating CLHAS tablets (Thérien-Aubin et al., 2008; Wang et al., 2010; Thérien-Aubin & Zhu, 2009). X-ray microtomography has been used to investigate the dynamic behavior of swelling tablets (Laity & Cameron, 2010; Laity et al., 2010). With the help of these novel technologies, we can investigate the internal properties of hydrating tablets more easily. In the near future, increasing investigators will do correlated researches and further insight into the swelling behavior of starch-based tablets will be obtained.^{Figure 4}

Figure 4. SEM top view micrograph of radial cross-sections of CLHAS-based tablets (Chauve et al., 2007). (A) 0-min swelling; (B) 15-min swelling; (C) 60-min swelling; (D) 150-min swelling; and (E) a close view of the 15-min swelling tablet. Four concentric domains are seen indicating a distinct evidence of membrane formation. Reprinted from Carbohydrate Polymers, Vol. 70, Chauve G, Ravenelle F, Marchessault RH, Comparative imaging of a slow-release starch excipient tablet: evidence of membrane formation, pp. 61–67, Copyright (2007), with permission from Elsevier.

Declaration of interest

The authors report no declarations of interest.

This research was supported by National Key Technologies 356 R&D Program of China (2012BAD37B01), Research Fund for the Doctoral Program 357 of Higher Education of China (20100093110001), 111 Project-B07029 and PCSIRT0627.