This document reviews recent advances in using modified starches as excipients in extended-release tablets. It discusses various starch derivatives used for this purpose, including retrograded starch, enzymatically modified starch, substituted starches like carboxymethyl starch and starch acetate, cross-linked starch, and grafted starch. Key factors influencing drug release from tablets containing these starches are summarized, such as crystalline structure, specific surface area, degree of substitution, and cross-link degree. The document concludes that physical or chemical modification and enzymatic hydrolysis can be used to control drug release from starch-based tablets by influencing gel formation and digestibility.

1. Recent advances of starch-based
excipients used in extended-release
tablets
Karthick Ravichandran.
Ⅰ st M.pharm ( Industrial Pharmacy).
JSS College of Pharmacy, Ooty

2. 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 compatibility 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 .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.

3.  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 , 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, 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 , and temperature cycling elevates the
pasting temperature and viscosity of retrograded starches compared with isothermal becomes more prominent
by temperature cycling rather than isothermal storage .

4. ⁎ 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 effects of retrogradation on the drug release from retrograded starch-based tablets were further
investigated by Yoon’s research group . 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.

5.  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 Pullulanase and isoamylase enzymatically
hydrolyze the α-1,6 glycosidic bonds of amylopectin selectively.
⁎ The enzymatically modified starch extended the release of drugs at an almost constant rate . 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.

6. ⁎ 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 1.0m₂/g, the
tablets will rapidly disintegrate and show a faster drug release.
⁎ A specific surface area of 1.5m₂/g is required in order to obtain a zero-order release Our research
group recently investigated the extended release properties of amorphous debranched starch (ADBS)
derived from pullulanase enzymatic modification .
⁎ 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 amorphous debranched starch 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 Fiskian diffusion. We confirm amorphous debranched starch (ADBS ) is able to be
used in oral tablets to extend drug release of drugs.

7.  Substituted starches:
⁎Substituted starches are prepared by esterifying and etherifying the hydroxyl groups of glucose units,
such as acetylated starch carboxymethyl starch (CMS) hydroxyethyl starch, hydroxy propylated starch
and phosphate starch .
⁎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.
⁎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.
 Carboxymethyl starch:

8. ⁎When the CMS tablets were transferred into a high pH fluid (SIF[Simulated intestinal fluid ], 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 .
⁎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) and amylose content on the release kinetics of small bioactive agents from CMS matrix
tablets

9. Physical appearance of CMS- (high
amylose content) based tablets with
different DS incubated in SGF for
different time
(A): High amylose starch (HAS)
without carboxymethylation (DS 0);
(B): CMS with a DS of 0.09 (DS
0.09);
(C): CMS with a DS of 1.23
(DS 1.23).

10. Influence factors Summary
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.
Geometries of tablets 1. The release time of the larger CMS tablets is longer.
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.
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.
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.
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.
Investigations of carboxymethyl starch used in extended-release matrix tablets:

11. ⁎ Starch acetate (SA) is a film-forming polymer produced by acetylating native starch Unlike other
modified starches, SA is less hydrophilic due to the hydrophobic nature of acetoxy substituent .Highly
substituted SA has been introduced for directly compressed tablets as a pharmaceutical excipient .Highly
substituted SA (DS 2–3) is soluble in acetone, chloroform and other organic solvents.
⁎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.
⁎ 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 .
 Starch acetate:

12. ⁎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 .CLHAS (Cross-linked high amylose starch ) is generally
derived from the cross-linking of high amylose starch (70% amylose, 30% amylopectin) with epichlorohydrin or
phosphate. CLHAS (Cross-linked high amylose starch) tablets are of high drug loading and quasi zero-order
release profiles. Compared to other excipients, CLHAS (Cross-linked high amylose starch) is more suitable for
hydrophilicmatrices preparation.
⁎CLHAS(Cross-linked high amylose starch) tablets swell in aqueous medium, yielding an elastic gel layer on the
surface of tablets 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 Cross-linked amylose (CLA) with low crosslinking degree shows intriguing
mechanical and sustained release properties.
 Cross-linked starch:

13. ⁎Unlike other polymeric matrices, (CLA)Cross-linked amylose tablets can no longer control drug release with
increasing crosslinking degree . High- crosslinking degree (CLA)Cross-linked amylose excipient outweighs others as a
binder or disintegrant, which is closely related to the network organization.
⁎Nevertheless, the network organization of high- crosslinking degree CLHAS (Cross-linked high amylose starch)
entraps more water molecules, which promotes the swelling of tablets and accelerates the release of drugs.

14.  Grafted starch:
⁎ Modifying natural polymers chemically by grafting has attracted considerable attraction due to the
integrated advantages of natural and synthetic polymers .Modifying a host polymer by the graft
copolymerization of guest monomers, such as ethyl methacrylate, acrylamide , methacrylic acid and acrylic
acid , brings about innovative and desirable properties.
⁎ Graft copolymerization offers novel and eligible properties , during which 3D gel network structures are
produced due to the participation of hydrophilic or hydrophobic groups in the guest monomer . 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 . Meanwhile, grafted starch, which is a hydrophilic matrix, swells in aqueous
media and is appropriate for preparing oral extended release dosage forms .

15. Modified
starch
Major influence factors
Retrograded
starch
Crystalline/Amorphous
structure;
temperature.
Debranched
starch
Specific surface area;
amylose/amylopectin
content; additional excipients.
Carboxymethyl
starch
Amylose content;
protonation ratio
(PR); degree of
substitution (DS).
Starch acetate Degree of substitution (DS); SA
concentration; drug type.
Cross-linked
starch
Cross-link degree (cld).
Crystalline/amorphous structure
Grafted starch Graft copolymerization;
drug type.
Tablets structural
features
Drug release
characterizations
Denser gel; less swollen and more
enzyme-resistant structure.
A constant drug release
for over 6 h.
A slow penetration of a solvent front
into the tablet; good compatibility.
An almost constant (zero-order) drug
release; a swelling controlled
Solvent activated
A pH sensitive hydrophilic matrix;
lower pH inducing a fast swelling;
stable gel layer formed at the presence
of Na+ ion.
A sustained release property (DS 0.1–
0.2); a delayed release property
(DS 0.9–1.2).
Less hydrophilic matrix; cracks formed
on the central horizontal plane of the
tablets.
Fickian diffusion.
A gel layer rapidly formed on the
surface of the tablets.
A quasi zero-order release.
A grafting chain derived acrylic layer
led to enzymatic resistance and
Hydrophobic behavior.
Fickian diffusion is the principal
mechanism in most formulations.
To some drugs, the release is
an anomalous transport.
Comparison and contrast of different starch derivatives used as extended-release tablets excipients:

16. 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 . 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.

17. References :
Recent advances of starch-based excipients used
in extended-release tablets: a review
Yan Hong, Guodong Liu & Zhengbiao Gu
To cite this article: Yan Hong, Guodong Liu & Zhengbiao Gu (2016) Recent advances of starchbased
excipients used in extended-release tablets: a review, Drug Delivery, 23:1, 12-20, DOI:
10.3109/10717544.2014.913324
To link to this article: https://doi.org/10.3109/10717544.2014.913324

18. THANK YOU