INTRODUCTION:

Starch is mainly principal form of carbohydrate ¹ and in its native form it exists as a semi-crystalline molecule, isolated from various botanical sources with minimal treatment to retain the intrinsic properties of starch². Chemically starch is made up of glucose polymers that is principally branched in two molecular forms viz. linear (amylose) designed by β-1,4-glycosidic linkages³ and secondary diverged (amylopectin) formed by β-1,6-glycosidic linkages⁴. The various physicochemical and functional properties of starch have attracted researchers. It's being used as a pharmaceutical excipient in a variety of drug delivery systems and formulations⁵. The ideal properties of native starch like smooth dryness⁴, whiteness and ability to impart gelling and supreme viscosity⁶ make it idyllic for pharmaceutical application. It is biodegradable⁷, readily available, and having low costs⁸ than the other synthetic polymer.

Starch is being used in many formulations and it varies as per need of dosage form, like as a glidant⁹, binder, disintegrant, thickening agent, bulking agent. Maize and potato starches have been in common use and recently cassava starch appeared in the British pharmacopoeia as an official starch for use as binder¹⁰. Though native starch is an excellent raw pharmaceutical excipient but has limited industrial application because of some undesirable properties like processability and solubility in common organic solvents¹¹, retrogradation and syneresis, low shear stress resistance and thermal decomposition¹² and hence superlative functional characteristics can’t be achieved through native starch. Hence this limitation can be possibly overcome by physical, chemical, genetic engineering or enzymatic modification of native starch to achieve and enhance the desired functional properties¹³. M. Teja Krishna et.al (2012), have explained that sweet potato starches retrograde very slowly than corn and wheat starches, but similar to potato starch¹⁴. The genetic engineering modifications are mainly applied to alter the ratio of amylopectin to amylose and their structures for specific applications, simultaneously physical adjustments in structure of starch are chiefly done to enhance the granule size and water solubility¹⁵. The various chemical adaptations in the molecular structure of starch enables more options for functionalization of native starch and relatively broadens the pharmaceutical application with the help of new emerging chemical techniques¹⁶.

Method of Starch Modification:

Modification of native starch is attained by various physical, chemical, enzymatic, and genetic adaptations which ideally tends to change and significantly improve the functional properties of simple starch and these modifications enables its utilization for several pharmaceutical purposes as an excipients both alone and in conjunction with active moieties¹⁷. The modifications help in improving the flow and compressibility characteristics of native starch which makes it more suitable for drug delivery systems. Among all types of alternations chemical modifications is one type which involves treating the starch and modifying it in presence of one or more chemical substance¹⁸.

Chemical Modification:

The various techniques involved in chemical modifications are acid hydrolysis, cross-linking, acetylation, dual modification, oxidation, and grafting. Chemical modification basically works by addition of new functional groups on the backbone of starch and imparting characteristic attributes to starch^19,20. Traditionally used chemical modifications techniques include esterification and etherification, cationization²¹, oxidation as well as crosslinking and hence introduction of various functional groups like acetyl groups ultimately leads to structural reorganization because of steric hindrance and repulsion of the starch molecules which enables the percolation of water in amorphous regions and causing enhanced solubility¹².

Rational Behind Chemical Modification of Starch:

Due to presence of three hydroxyl group adjacently to carbon atoms at 2,3 and 6 at each anhydroglucose unit (AGU), avails easy chemical modification of starch ²² and further linking of various functional groups. Mainly the possibility of chemical modification depends upon the degree of substitution (DS) and the type of functional group applied. The maximum permissible DS for starch is 3.0 because of each glucose unit along a starch chain has only three hydroxyl groups²³.

Acetylation of Starch by Chemical Modification Using Various Acetylating Agents:

The biodegradable existence of starch, the presence of certain functional groups, and the granular (macroscopic) structure have all played a role in the chemical modifications that starch is susceptible to substitution reactions²⁴. The esterification can be done with glacial acetic acid or acetic anhydride as an acetylating agent in the presence of sodium hydroxide, pyridine or sulphuric acid as a catalyst. The cost effective and regulatory safer chemical modification practice is acetylation of the starch by process of esterification with acetic anhydride, this addition of acetyl group in native starch prevents retrogradation by intruding the linearity of amylose and/or segments of the amylopectin branches²⁵. When potassium carbonate was used as an activator in the reaction of starch with acetic anhydride, a high degree of substitution was obtained. Starches could be acetylated on a micro scale without the use of a catalyst. The method includes heated the native starch with acetic acid for 2-4 minutes at a temperature of 179–181°C, resulting in a homogeneous mixture²⁴. Scientists optimise the reaction conditions such as reaction time, reaction temperature, catalyst concentration for better substitution, so that it will gives the desired hydrophobicity to the modified polymer, and all these factors also affects the degree of substitution. Here authors are tried to enlist some of interesting examples on chemical modification of starch. Table 1 depicts the some of the modification processes carried out for the acetylation of starch.

Applications of Acetylated Starch:

Modified starch finds its various pharmaceutical application as compared native starch, it mainly imparts properties like Controlled/ Sustained release polymer, swellability, excellent compressibility, higher crushing strength, better flow properties²⁶. The sustained release property causes entrapment of drug inside the matrix and tends to slow diffusion of drug moieties by mechanism of swellability stimuli response and along with reduced enzyme sensitivity during gastrointestinal digestion²⁷. The poly-anionic behaviour of acetylated starch in hydrogels enables prolonged release of drugs from systems and imparting swellability characteristics²⁸. Targeted drug delivery can also be achieved through modified starch because of high hydrogen content which enables formulation of pH responsive drug delivery system²⁹. As compared to microcrystalline cellulose this modified starch explored to have higher compressibility and simultaneously having better flow and compressibility properties, higher crushing strength along with less friability^30,31. Acetylated starch enhances the bioavailability of poorly water soluble drugs and macromolecules like insulin³².

The gelatinization phenomenon is generally observed in acetylated starch, when cooled the amylose chains released from the starch granules tends to re-associate with each other and with branches of amylopectin and commonly known as retrogradation. Acetylation of starch reduces the tendency of these starch solutions to undergo clarity, texture, and syneresis deterioration when stored at low temperatures³³. Because its functional qualities are less adaptable under process conditions like high temperature, shear stress, and contact to acidic fluids, starch's natural structure might be inefficient, limiting its usage in industrial applications³⁴. Hence acetylated starches facilitate higher stability and resistance to retrogradation, enhanced granular size, swelling power, and water absorption capacity of acetylated starch provides good flow and compression properties^35,36. The attributes like enhanced flow, disintegration, direct-compression, formation of stable gels in hot and cold water gained by modification of starch expands its pharmaceutical application ³⁷ and functions and making it smart excipient for efficient delivery of drugs in both conventional and novel drug delivery systems³⁸.

Pharmaceutical Formulations Using Acetylated Starch:

Scientists are looking forward to use this acetylated starch for the preparation of pharmaceutical formulation. Many a times for controlled release purpose researcher have to use the synthetic polymer, but with this modified starch final formulation gives satisfactory results. Researchers are also working on optimizing these polymer concentrations in various formulations. Here authors are tried to compile some examples where acetylated starch used as a polymer for the preparation of pharmaceutical formulation. It seems from all these examples that the formulation using acetylated starch, the slower drug release. Let’s have a look on Table 2, which depicts some examples on acetylated starch, and it has been utilised since more than decades.

Scientists also modified the starch other than the acetylated as per their needs. Some of the modified starches other than acetylated are enlisted here. Akash V et al. (2018), have modified the starch to calcium starch by gelatinizing it with NaOH and crosslinking using calcium chloride. They have used this retardant polymer for the preparation of sustained release tablet using Metoprolol HCl as a model drug and evaluated for pre-compression, post compression parameters and in-vitro release kinetics assessment of tablets³⁹. Subhashis Debnath et. al. (2020), have modified the potato starch to starch citrate to check the disintegrating efficacy of it. Where they have used paracetamol as a model drug and formulate the tablet using the starch citrate as a disintegrant⁴⁰. Renata Baranauskienė et al. have modified potato starch using hydroxypropylation using propylene oxide followed by esterification with octenyl succinic anhydride (OSA) to produce modified potato starch derivatives, and in that modified starches they have encapsulated caraway essential oil (EO) using spray-drying technique. The EO microencapsulation effectiveness in various adjusted starches, the maintenance of unstable fragrance compounds, emulsion molecule size and the microstructure of splash dried exemplified powdered items, just as the compositional smell changes occurring during handling and capacity as long as 8 months have been estimated⁴¹. Prasanthi NL and Rama Rao N (2010), have modified the starch to starch phosphate, wherein hydroxyl group chemically replaced with phosphate group. They have formulated and evaluated tablets containing Lacidipines as a model drug employing LAC-SP binary systems and evaluated for dissolution rate and efficiency⁴².

Table 1: Acetylation of starch using various methods

Authors and Yr.	Objective of work	Key findings	Ref.
Kemas et al. (2020)	Determined the impacts of modiﬁcations on the structural and rheological properties of starch from Plectranthus esculentus (Pesc) tubers modified using a series of techniques which include carboxymethylation, acetylation, xerogel formation, oxidation, as well as acetylation accompanied by xerogel initiation and acetylation accompanied by oxidation. Shear thinning was seen in the natural starch and its derivatives.	Finally, they came to the conclusion that the acetylated starch derivative had practical relevance in terms of shelf-life and stability in the pharmaceutical and food industries.	43
Abraham Calderon-Castro et al. (2019)	Employed an extrusion procedure to modify maize starch by acetylation and succinylation, using AA and succinic anhydride, respectively.	The optimization was carried out using a design experiment, with the independent variables being barrel temperature (BT), screw speed (SS), and reactant concentration (RC), and the dependent variables being water absorption index, degree of substitution, and water solubility index. They set the RC to 7.88 percent, the BT to 80 degrees Celsius, and the SS to 100 revolutions per minute, with a DS of 0.2 and a water solubility index of 6.15 percent. Contrary to popular belief, the RC for succinylated starches is 1.12%, BT is 80°C, and SS is 126 rpm, with 0.05 DS and WSI is 7.92%. These findings demonstrated that it is possible to achieve safe-for-food use acetylated and succinylated DS levels are modest	44
Venkateswara Rao et al (2017)	Used acetic anhydride and NaOH to modify potato starch.	Acetylated starch has a DS of 1.60, making it hydrophobic and insoluble in acetone and chloroform	45
Mendoza (2016)	Evaluated the effects of esterification on the structural, morphological, as well as functional qualities of native starches "Dioscorea spp." using AA as an acetylating agent. They made a 42.5 percent starch suspension and stirred it for an hour at 30 degrees Celsius. As a catalyst, they employed NaOH and regulated the pH to 8.0–8.2 using the same. Following that, acetic anhydride was gradually added, keeping the pH between 8.0 and 8.4. The suspension was regulated to a pH of 4.5 with 0.4 N HCl once the reaction period was completed. The starch was washed, dried, crushed, then sieved, and FTIR, X-ray diffraction, and scanning electron microscopy were used to analyse it.	Thus, the finding revealed that “introducing acetyl groups into the starch structure resulted in a lower gelatinization temperature and a greater tendency for retrogradation”	34
Raj V. and Prabha G. (2016)	Used AA as an acetylating agent and pyridine as a catalyst to modify native cassava starch.	Cassava starch was dried in an oven for 20 hours at 45–60 degrees Celsius before acetylation. In a pyridine medium, dried starch was combined with acetic anhydride in 1:4 ratios for 3 hours at 120 degrees Celsius. The starch was extracted, filtered, and dried in a vacuum oven after being precipitated with ethanol. Finally, the modified starch was crushed and sorted in a sieve (#50 mesh) to obtain a uniform particle size, then stored in desiccators until further research.	46
S.H. Mahmoudi Najafi et al. (2016	Modified maize starch using the esterification process, with AA as the acetylating agent & sulfuric acid as that of the catalyst. The reaction could be carried out with or without the use of a catalyst. For obtaining acetylated corn starch, they adjusted two reaction parameters: reaction temperature and the molar (m) ratio of AA to corn starch.	The researchers discovered that as the reaction temperature climbed from 37 to 100 ⁰C, the DS increased. They went on to say that greater temperatures increase the diffusion of esterifying agents and the expansion of starch granules, which destroys the crystalline portions of the starch granules and causes them to become amorphous. "Acetylation of starch is an exothermic reaction, and temperatures above 100°C are unfavourable for the absorption of the eacetylating agent by the starch and the creation of active reaction centres," they added. When the mAA:mCS ratio rises, the DS rises as well. This could be attributed to increased interaction between the starch molecules and the AA molecules.	47
Josiane Bartz et al. (2015)	Investigated the effects of the AA in a fluid arrangement somewhat on degree of acetylation, physical characteristics, other attributes, and enzymatic weakening on rice starch acetylated at a rate of up to 2.5 g/100g.c On a dry basis, it was acetylated with 5g, 10g, and 20g of AA per 100g of starch.	Acetylation enhanced viscosity, retrogradation, and pasting temperature while lowering gel hardness, adhesiveness, and gumminess.	48
Nutan MT et al. (2005)	Using the paste disintegration technique, authors acetylated native corn starch containing about 25% amylose to obtain acetylated starch with a high DS. The starch was pregelatinized and in a medium of 400 g pyridine, 200 g AA was used to acetylated 50 g pregelatinized starch. The reaction was carried out in a flask at 100°C for 4 h under a reflux condenser. The resultant was precipitated in adequate alcohol, filtered and washed with alcohol, dried in the air, and passed through a sieve. The DS-Value has been determined.	Gel permeation chromatography with two PLgel Mixed-B columns (Polymer Labs Inc., Amherst, MA) was used to estimate the molecular weight of acetylated starch, which was calibrated with a polystyrene molecular mass reference. A combination of dimethyl acetamide and sodium nitrate was employed as the mobile phase, which was heated to 100°C and flowed at 1.0 ml/min. An RI detector was used to detect elutes.	49

Table 2: Pharmaceutical Formulations Using Acetylated Starch

Authors and Yr.	Objective of work	Key findings	Ref.
Colussi R et al., 2017	Have prepared films of acetylated rich starch with varing levels of amylose. For acetylation they have used chemical modification method using acetic anhydride as acetylating agent	The films were characterised to the mechanical, water vapour barrier, thermal, and biodegradability properties. The acetylation decreased the tensile strength and increased the elongation of the film. High and medium amylose starches films had no significant difference in degradability. However, acetylated starch films exhibits a more rapid degradation as compared to native starches films.	50


El Halal et al (2017)	Performed the study on films based using acetylated starch and cellulose from barley	In that they revealed the use of acetylated starch with a high degree of substitution in the preparation of packaging are required, in considering of acetylated starches with a low degree of substitution were not effective in a reduction of the water vapor permeability	51
S.H. Mahmoudi	have acetylated corn starch using varying degrees of substitution (DS) and utilised ciprofloxacin as a model drug to nanoprecipitate	Acetylated nanoparticles with a diameter of 312 nm and a DS of 2.00 and a water: acetone ratio of 3:1, according to the findings. Increasing the DS in starch acetate increased the EE from 67.7% to 89.1%, while increasing the water/acetone ratio from 1:1 to 3:1 increased the EE from 48.5 to 89.1%. The A-type pattern of native starch was totally changed into the V-type pattern of acetylated starch, according to X-ray diffraction. The SEM revealed that after nanoprecipitation, the varied sizes of holes generated on the esterified starch granules were completely changed into uniform-sized spherical nanoparticles The absorption of CFx in various DS has a significant impact on the zeta potential values of the acetylated nanoparticles. For acetylated nanoparticles, a high EE was obtained with a high DS..	47
Najafi et al. (2016)			47
Tuovinen L et al., 2004	Have prepared starch acetate microparticles for drug delivery into retinal pigment epithelium (RPE)-in vitro study	Cellular uptake of the starch acetate microparticles was analysed using flow cytometry and confocal microscopy. Degradation of starch acetate films by homogenate of lysed RPE cells was determined by gel permeation chromatography. The results showed that the starch acetate microparticles are taken up by the RPE cells and the polymer can be degraded by the enzyme in these cells, as well as these starch acetate microparticles may be suitable for the drug delivery to the RPE.	52
Tuovinen L et al., 2003	Studied and evaluated drug release from the starch acetate (SA) microparticles (SA mps) and SA films using Timolol, calcein, and bovine serum albumin used as model drugs	Concluded that the slow release of different molecular weight model drugs from the SA mps and films as compared to fast release from the native starch preparations. DS of SA, physicochemical properties of a drug and the presence of enzymes can all affect drug release profiles from SA based preparations.	53
P.S Rao and R.M.Beri, 1955	Have tried to acetylated tamarind seed jellose. The hexa, duodeca and hexadeca acetyl derivatives of tamarind seed jellose have been prepared by treatment with acetic anhydride under different conditions. Effect of Glacial acetic acid also checked	Acetylated derivatives give fairly strong flexible, glossy and transparent films, which adhere to glass, metallic and also wooden surfaces. They may be also useful as thermoplastic resins on account of their wide melting ranges.	54

Future scope:

Recently in the pharmaceutical industries the modified starch are used for different purposes, such as etherified starch were successfully used in fast disintegrating film, as well as fast disintegrating tablet. One of the industries working on it is ROQUETTE with the brand name of Lycoat⁵⁵. So working on controlled and or sustained release purpose, acetylation of the starch could give the desired output as the formulator wants. Since starch is naturally occurring, biodegradable, cost effective and easily available polymer, hence its acetylated derivative may provide the same properties. Therefore future market for the controlled and or sustained release purpose would hopefully look forward to acetylated starch.

CONCLUSION:

Both starch and modified starch is a part of pharmaceutical industry since long time. For the modification of the starch by the chemical method and especially using the acetylation method the scientists are working on various acetylating agents such as glacial acetic acid and acetic anhydride, among them acetic anhydride may be the strong acetylating agent since it contains two acetyl groups which may helps in giving the high degree of substitution. As we know that the starch contains hydroxyl groups at the position of 2, 3, and 6, therefore for high degree of acetylation acetic anhydride is best option. Depending on the degree of substitution of acetyl group on the backbone of starch the hydrophobic properties varies, therefore strong acetylating agent plays important role. Acetic acid is used under the category of green solvent, so it may help to modify the starch by green synthesis. In the modification method catalyst play an important role, as it increases the rate of reaction. Mostly NaOH, pyridine, sulphuric acid are used as catalyst. Parameter of the esterification method for modifying the starch has been optimized by the scientists. Literature showed that optimised temperature range from the 30-120 ⁰C is mostly used by the scientist. Some of scientists stated that “esterification of starch is an exothermic reaction, the higher temperature (>100 ◦C) is unfavourable to the absorption of the esterifying agent by the starch and formation of active reaction centers”. Optimised reaction time for the reaction completion may be from 30-60 minutes. Also from the literature it observed that the morphological, structural and functional properties of the acetylated polymer get changes which favours the polymer for selection of the controlled and or sustained release pharmaceutical formulation. From the current review authors can be concluded that modified starch has been tried to be used as polymer for the formulations of nanoparticles, microparticles, films, tables and other dosage form. It is being used in many formulations and it varies as per need of dosage form, like as a binder, disintegrant, thickening agent, bulking agent. The acetylated starch could facilitate higher stability and resistance to retrogradation, enhanced granular size, solubility, swelling power, also water absorption capacity of acetylated starch could provides good flow and compression properties. But it is not explored yet in many ways like in controlled release or sustained release formulation. Therefore it is a need of hour to explore the acetylated starch as an alternative to the synthetic controlled release or sustained release polymer.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation

ACKNOWLEDGMENTS:

We would like to acknowledge Chhatrapati Shahu Maharaj Research, Training and Human Development Institute (SARTHI), Pune, Maharashtra, India, for providing financial support through Chhatrapati Shahu Maharaj National Research Fellowship (CSMNRF-2019) to Vidyadevi Bhoyar and we also would like to acknowledge Government of India, Ministry of Science and Technology, Department of Science and Technology (DST), India for their financial support to Sagar Trivedi trough DST-INSPIRE Fellowship (IF 190486). Authors are grateful to University Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, for providing necessary facility.

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Received on 23.08.2021 Modified on 11.01.2022

Research J. Pharm. and Tech 2022; 15(11):5337-5343.

DOI: 10.52711/0974-360X.2022.00899