ph- Responsive natural polymers:

The utilization of natural biodegradable polymers prevails to be more fruitful due to:

· Wide availability in nature

· Good biocompatibility

· Capacity to be readily fabricated by simple techniques [15]

This highlight the efficiency of most synthetic biodegradable polymers that have been developed for biomedical application [11,16]. pH-responsive self-healing gel system has been prepared using some natural polymers that offer standard efficacy [10,17-19]. The natural polymers that are abundantly used are dextran, hyaluronic acid, alginic acid, chitosan and gelatin (figure 5). These polymers can provide even better transporters for drug delivery if they undergo appropriate chemical modification. The grafting or joining of responsive polymers onto polysaccharides backbone is another famous development technique. The cross-linking agents have been used to develop hydrogels of these polymers in many research studies making the chitosan the most vaguely studied polymer of such species [10,20,21]. Table 2 natural origin polymers(FDA approved)according to their administration route are listed. [22]

Chitosan:

N- DE acetylation of chitin yields the chitosan which is a Polyaminosaccharide. Its composition and tight intramolecular H-bonding between amino groups and hydroxyl groups present on the structure of chitosan are responsible for its thermostability. Chitosan being a weak polybase used extensively in hydrogel smart delivery systems due to the presence of more amount amino groups on its chain that supports pH-sensitivity properties which is reversible. A protonation of the amino groups occurs at pH˂6.5 that makes chitosan soluble in water and inorganic acid, like formic, tartaric, acetic and citric acids [22,23]. In oral dosage formulation, it is used as an important excipient having good biocompatibility and minimal toxicity. An angle of repose of powder blend is effectively reduced by chitosan in comparison to traditional excipients (e.g. lactose, starch mannitol) which enhances the fluidity of the powder blend. Due to water uptake properties which provides potential benefit in using as a diluents, binder, lubricant, and disintegrant in preparation of pharmaceutical formulation [ 15,24,25] Generally, a crosslinking technique by glutaraldehyde is used to achieve a particulate drug delivery [15, 26]. It has potential antibacterial property against a wide range of a microscopic organism. There is leakage of intracellular contents due to adherence of positively charged chitosan to the negatively charged cell wall. There is inhibition of mRNA responsible for the synthesis of proteins where chitosan bind with DNA of the microorganism. This phenomenon occurs by penetration of chitosan to the core of bacteria which interfere with mRNA and protein synthesis. Because of the property like antibacterial, it is mixed with different polymers while preparing pharmaceutical dosage forms [27, 28]. Due to gel-forming nature at low pH, the antiulcer and antacid property where ulcerogenic drugs like aspirin can be administered effectively in combination with chitosan [15, 29]. Chitosan plays important role in reducing gastric mucosal injury caused by diclofenac sodium [15, 30].

Alginates:

Alginates are hydrophilic polysaccharide carbohydrates derived from marine sources and widely found in nature. Due to easy fabrication into particulate carriers, susceptible to sterilization and storage have been used abundantly in controlled release drug delivery system [22, 31]. It composed of L – glucuronic acid and D –mannuronic acid which is an anionic block copolymers. There are two distinct ways where alginate can behave as stimuli-responsive polymer. The first one is by ionic interaction with divalent metal ions (ca2+) in which EDTA (chelating agent) or alkaline buffer (phosphate) can comfortably eliminate calcium divalent metal ions producing divalent calcium (ca2+)stimulus hydrogel system. The next way is by hydrogen bonding at minimal pH value (pH<2) regarding on pKa values for acidic groups of carboxylic acid in Mannuronic acid (pKa 3.38) and Glucoronic acid (pKa 3.65) [22, 32]. In the drug delivery system, the hydrophobically altered alginates have wide application. There is an enhancement in the efficacy and target action by encapsulating proteins and bioactive factor inside cross-linked alginates gels thus research has been for the development of alginate based protein drug delivery system [11, 33]. The pharmaceutical preparation which is prepared from the alginate based (alginate gels) have demerits of slow degradation and as well as have weak cell adhesion on alginate gel. The dosage forms synthesized via mixing sodium alginate and chitosan (natural polymers) have good encapsulation efficiency which results in improved discharge profiles of protein. Alginate-based preparation at low pH (stomach environment) constricts thus entrapped drug doesn’t discharge. For instance, insulin is susceptible to oral administration so, in order to improve liposomal technique is adopted where insulin is added to the liposome-forming Lipo-insulin preparation. This lipo-insulin system gains the ability to encapsulate in the alginate-based system. The conformational design and insulin potency will be protected via the liposomal hydrated medium and ease of penetration through the biological membrane will be enhanced by an outer region of lipid. Oral administration of lipo-insulin – loaded alginate – chitosan decreases the blood sugar level of rats having diabetic [11, 34, 35]

Hyaluronic acid:

Hyaluronic (Hyaluronate) is polysaccharide in nature, it composes of D – glucuronic and N – acetylglucosamine made up of disaccharide units connected by β (1,4) and β (1,3) glucosidic bonds. It can be found widely in a living organism (vertebrate organism), microorganism and bacteria. Due to its abundant existence, many pharmaceutical preparations utilize hyaluronic acid as excipient [11]. Hyaluronic acid extensively exist in synovial fluids and at the surface of cartilage. It is an important carbohydrate constituent present in extracellular matrix [22, 36]. Due to properties like, lubrication and shock absorber has been extensively used in osteoarthritis (joint pain) which enhances lubrication at joint surfaces. It also block chondrolysis of chondrocyte in cartilage and maintain cartilage matrix [22, 37]. Hyaluronic acid can play a major role. It has also been extensively for drug delivery [22, 36]. The matrix of hyaluronic acid is used with cross-linking with glutaraldehyde [22, 38], carbodiimide [22, 38], or polyethylene glycol diglycidylether (PEGDG) [22, 37] to inhibit rapid degradation and clearance. Many techniques have been invented for the formation of HA HGs complex having photo-cross-linking and disulfide – cross-linking because of its potential role in vivo and benefits in tissue engineering [11, 39]. There is the formation of semi-interpenetrating networks on the addition of HA to collagen and inside micro fluidic networks, adhesion of endothelial cell leads in the generation of blood vessel formation [11, 40].

Figure 5: Natural origin polymers.

Multi – responsive polymer:

The synthesis of different materials that counter concurrently to various stimuli like temperature, magnetic fields, pH etc, can be formulated and implanted additionally to single response polymer. A polymer that is more peculiar and governable can be synthesized by combining two or more properties. By copolymerization of monomers containing hydrophobic and ionizable functional groups along with monomers having magnetic group can result in temperature and pH-responsive polymers bearing magnetic properties. For instance, PMEMA and PDMA are the polymers having both temperature and pH-responsive properties. Numerous multi – responsive copolymer can be developed by merging two or more monomers that respond to different stimuli. By engineering one block that is pH-responsive and next block being temperature responsive, the multi-responsive polymer can be manufactured. Because of its lower critical solution temperature (32⁰c) in water, PNIPAm is widely used as a thermo-responsive block [10, 41]. Few multi-responsive polymers are listed in Table 3 below

Table 2 :Drug products (FDA Authorized) and Its Inactive polymeric Ingredients

Polymers (Natural-origin)	Synthetic Polymers (Polyester-Based)
Human albumin ( for IV, SC, oral uses)	KOLLIDON VA 64 ( for oral use)
Starch (for oral, IM, IV, topical)	PEG ( for oral, respiratory, topical, IM, IV, Ophthalmic uses)
Hyaluronate ( for intraarticular, IM, Intravitreal,topical uses)	PLGA (for IM, SC uses)
Collagen ( for topical use)	sodium pyrrolidone carboxylate ( for topical use)
Gelatin ( for IM, SC, IV, oral, topical use)	Poloxamer ( for oral, topical, IV ophthalmic, SC uses
Alginic acid ( for ophthalmic and oral uses)	PVA ( for auricular, IM, intraocular use)
	Povidone ( for oral, intraarticular, IM, intrauterine, topical, SC, respiratory, ophthalmic uses)
	Polyvinylpyrrolidone ethyl cellulose ( for oral use)
	PLA ( for IM use)

Techniques for the preparation of ph-responsive polymers:

Reversible addition – fragment chain transfer(RAFT) polymerization, nitroxide – mediated radical polymerization(NMP), atom transfer radical polymerization (ATRP), Group exchange polymerization (GTP), anionic polymerization, cationic polymerization, free radical polymerization are the various polymerization techniques for preparation of vinyl-based pH-responsive polymers [10,71].Emulsion polymerization is one of the most frequent and well known synthetic routes for the preparation of pH-sensitive polymeric system, particularly microgel system. Emulsion polymerization, in contrast to bulk, solution or suspension alludes a unique procedure that adopts radical chain polymerization method to obtain latexes of narrow size distribution. Monomers (s), water – dissolvable initiator and emulsifier are the most common ingredients in emulsion polymerization [72, 73]. Surfactants play a vital role in shortcomings of emulsion polymerization at the point of phase separation, which should be removed at the end of the emulsion polymerization. There may be the formation of coagulants or flocculants of the latex due to the removal of surfactant either by dialysis or desorption method [72, 74]. Well – defined, core-shell nanoparticles can be synthesized by using this kind of emulsion polymerization. The prepared core-shell NPs contains poly (methyl methacrylate) (PMMA) core and P(MMA-co-EA) shell [11,75]. Production of latexes with high solid content, semi-batch emulsion polymerization procedure has been utilized in industry. For instance, through semi-batch emulsion polymerization using aerosol OT surfactant commercial hydrophobically altered base- soluble/ swellable emulsion ( HASE) were synthesized [72,76,77]. The base/ alkali soluble polymer contains a polymer backbone comprising Methacrylic acid (MAA) and Ethyl acetate (EA) of hydrophobic macromonomer to its backbone [72, 76, 78]. They are as a colloidal particle at low pH and the hydrophobic macromonomers form the viscous solution at high pH at which they are soluble. A little amount of cross-linker are introduced and the swelling/de swelling characters can be controlled by MAA and cross-linker contents in case of hydrophobically altered basic – swell able polymers [72,79]. Anionic polymerization and group transfer polymerization are another controlled polymerization technique utilized for the production of well-characterized pH-responsive polymers. Methacrylates are produced by the most appropriate polymerization system, group transfer polymerization. The utilization of this system is restricted due to strict reaction condition which is not appropriate for all monomers, for example, DMA[10, 80, 81, 82], DEA[10, 60, 82, 83], DPA[10, 61, 84, 58], and MEMA[10, 61, 84, 83, 85], have been produced utilizing GTP in diverse structures, for example, block[10, 61, 80, 81], star[10, 86], branched [10, 82] etc. In GTP, functional monomer like methacrylic acid can be used because of their labile protons that end polymerization. So, functional group should be masked using protecting groups to carry on polymerization that are promptly changed over back to functional species [10,80, 87]. CRP (chain polymerization) carry on even in the absence of termination reaction and chain transfer reaction. ATRP, NMP, and RAFT are noticeable among CRP technique in the production of pH-responsive polymers. For the controlled polymerization of various vinyl and acrylic monomers under the mild condition, ATRP is one of the most powerful controlled/living radical polymerization system [11, 88]. Due to impurities like moisture sensitivity and functional group resistivity, ATRP possesses resistance to these impurities. It has few limitations on the polymerization of acrylamide and its derivative, unlike ionic polymerization. Also, it has another advantage of ATRP, the polymers synthesized by ATRP technique can be used as large-scale initiator for further additional steps. The various architecture like block [10, 89], star [10, 90-92], gradient [10, 89, 93], brushes [10, 94, 95] and branch (co)polymers [10, 96] can be easily produced by ATRP technique so, this technique has been often utilized in the production of pH-responsive polymers.

In 1980, the first utilization of addition – fragmentation transfer agents were used to control radical polymerization [10, 97, 98, 99]. The well – defined (structured) macromolecular designs polymers with moderately low pol–dispersity index can be synthesized by Reversible addition-fragmentation chain transfer (RAFT) radical polymerization [11, 100, 101]. The achievement of control characters by RAFT polymerization is due to reversible chain transfer which reduces the number of radicals and subsequently diminishes the possibility of termination reactions [11, 102]. By ATRP and RAFT techniques, a polymer having mono – or multifunctional end groups can be synthesized. Different polymeric materials can be synthesized by modifying the groups in polymers. For instance, non – ionic PG2MA –b- PHPMA diblock copolymer has been prepared by Armes' group exhibiting pH-responsive characteristics. This behavior is because of the carboxylic acid RAFT agent which is used in the synthesis of polymers [10, 103]. The surface-initiated atom transfer radical polymerization (SI – ATRP) and surface initiated reversible addition – fragmentation chain transfer (SI- RAFT) are often used in the preparation of pH responsive polymeric brushes by simple adjustment of silicon and gold surfaces with ATRP initiator. By utilization of emulsion polymerization procedure distinctive size pH-responsive crosslink hydrogels (micro and nano-) can be prepared [10, 104, 105, 106, 107]. Well-characterized property and the approaches to get pH-responsive can be synthesized by these techniques, the polymeric chain may be linear homo or copolymers, amphiphilic block copolymers in a structure that form micelles, microgels, HGs, micro- or nanoparticles.

Applications:

ph – Responsive polymers and drug delivery system:

The human body has been designed to demonstrate a various range of pH (table 4). This range of pH can be utilized to target medicinal agents or drugs to a particular organ, body area, or the specific site to hit the target.

Table 4: pH values from several tissues and cell compartments

Cell / tissue compartment	pH
Tumor – extracellular medium	6.2 – 7.2
Golgi complex	6.4
Colon	7.0 – 7.5
Lysosome	4.5 – 5.0
Duodenum	4.8 – 4.2
Stomach	1.0 – 3.0
Blood	7.4 – 7.5

The ideal pharmaceutical systems, i.e., pH-sensitive polymers utilize these conditions to carry the drugs to specific parts like colon [108]. Enteric polymers are commonly used because they resist degradation in an acidic environment (low pH of the stomach) and release the drug in the alkaline medium of intestine due to the formation of salt. Commercially, many such polymers are already manufactured and have high demands like CAP produced by Wako Pure Chemicals Ltd, Eudragil-L, Eudragit-S produced by Rohm Pharma, GmBH (modification of methacrylic acid and methyl methacrylate) or CMEC produced by Freund Sangyo Co. Ltd., HP-50, and ASM from Shin- Etsu Chemical Co. Ltd(cellulose derivative),. Numerous polysaccharides have also been studied and the research is transforming into fruitful results. For example, polysaccharides like cyclodextrin, chondroitin sulfate, dextran, amylose, guar gum, pectin, chitosan, inulin have been experimented[109, 110,111].

A study/experiment by Mishra [112, 113] has revealed that HPMC-AS and Eudragit-P4135 F can be formulated into nanoparticles which carry a trait of acidic resistance or enteric coating that ensures delivery of drug to a specific site where there is a colon. Mishra tried formulating Metoprolol succinate with HPMC-AS and Eudragit-P4135 F which resulted in pH-sensitive nanoparticles that could be used as a targeted drug delivery system specifically for a colon. The delivery of drugs, proteins, peptides, etc., to a specific site, can be facilitated using different formulations that involve the use of pH-sensitive polymers. The pharmacological substances that are deteriorated or have negligible absorption in the acidic medium of the stomach and pH of intestine whereas favored by the gentle conditions of the colon can be produced using different pH-responsive polymers. These type of formulations can be useful for the local pathologies of the colon and systemic delivery. Apart from the targeted delivery, pH-sensitive polymer like Thermocoat L30D55 has been known to protect the products from environmental factors like temperature, humidity, light, enhancing the shelf life of products. PH-regulated Tulsion microspheres targeting the drug delivery in the colon is prepared using Thermocoat L30D55. Microspheres were prepared by quasi-emulsion spherical crystallization method with a combined mechanism of release. The major contributing factors for drug release were specific biodegradability of polymer and pH-dependent release [112, 114].

Another colon targeting formulation based on the pharmacokinetic study was done by Shi et. al., [112, 115] in which P9LE-IA-MEG) hydrogel microspheres were developed to show colon targeting property and efficacy in ulcerative colitis. Similarly, Agrawal et. al., [112, 116] used Eudragit L100, S100 to prepare the microspheres of Capecitabine as a therapy for colorectal cancer. This formulation aimed is to improving patient compliance and decrease the frequency of dosing.

pH sensibility is presented by a number of naturally occurring polymers like chitosan, albumin, gelati. From chitin, a cationic amino polysaccharide can be derived, i.e., chitosan. It is soluble in water at pH 6.2 acting as a cationic polymer and transforms into an aqueous gel as the pH increases. Since it has this mucoadhesive gel property, it can be utilized in oral or mucosal drug delivery. Chitosan has a positive charge [108, 117] it can also carry DNA (-ve charge) by fusion into its amino groups. Chitosan/glycerophosphate is a better option pharmaceutical system for development of efficient implants, because of its permeability as well as enhanced capability to control the release of drugs and macromolecules with poor water solubility. The insertion of paclitaxel in the glycerophosphate system of chitosan enhances the delivery of the drug at a sustainable rate which improves the inhibition of growth of cancerous cells EMT-6 [108, 118].

Gene carriers:

pH-sensitive polymers can be encouragingly used as non-viral gene carriers because the incorporation of naked DNA into cells is a tough job as the DNA is negatively charged and is massive in physiological conditions. For the gene delivery, DNA has to be condensed in charge balanced nanoparticles which are facilitated by gene delivery methods assisted by chemical means. Two major types are; one is liposome and the other is polycation. Elaboration on the use of poly (L-lysine) (PLL) and poly (ethylenimine) (PEI) as the best applicants for non-viral gene delivery has been reviewed by Godbey and Mikos [109, 119]. PEI can form complexes by condensing DNA in solution, that can easily be taken up by many cell types through endocytosis because it is a highly polycationic (synthetic) polymer. As mentioned earlier, Chitosan has also been extensively used as a DNA carrier, being biocompatible and resorbable cationic amino polysaccharide [109, 120, 121].

Hoffman's group has committed incredible efforts to the molecular machine of some viruses and pathogens and acquired novel targeted structures to effectively induce biomolecules to targeted intracellular sites. Fluctuations in the pH gradient of the endosomal region are detected by the molecular machine which in turn destabilizes the endosomal layer making it prone to destruction. Upgradation of the protein or DNA transportation to the cytoplasm from intracellular sites like endosome is carried out by this mechanism [11, 122, 123]. Besides that, another accessible technique is by grafting of a lipidic double-layered system (liposome) with a pH-responsive polymer (cationic), which holds the DNA molecules as a part of its interior system. In this manner, the balance of the negative charges of DNA is maintained by cationic polymers and then compress it to obtain nanoparticles having about 100nm diameter. Through a different mechanism than that of cationic polymers, the efficiency of DNA molecules is enhanced by the use of anionic polymers. Transformation of the hydrophilic state to a hydrophobic/lipophilic state is a characteristic property demonstrated by the anionic polymers which make the endosome layer to be unstable resulting in disruption [108, 124].

To enhance the condensation of the nucleic acid molecules, an additional cationic polymer is attached to the particle formed by the physical or chemical mixture of anionic polymers and DNA. The formed particles, therefore enter the particular cells by endocytosis and get changed to a lipophilic state causing the endosome layer to rupture, consequently delivering the content. The anionic polymer PPAA (polypropyl acrylic acid) or PEAA (poly ethacrylic acid) form the nanoparticle that enhances the stability of the formulation and promotes DNA transfection. PEAA (poly ethylacrylic acid) and PPAA (polypropyl acrylic acid) are the pH-responsive polymers used to carry genes. When the pH decreases to value between 5 and 6, PPAA and PEAA have enhanced hemolytic activity but do not confer any blood cell disorders at pH 7.4 [108, 125, 109]. They utilize hydroxyproline (collagen, gelatin, and different peptides) blended with a biodegradable polycationic polyester polymer named poly (trans-4-hydroxy-L-proline ester) to form a macromolecule along with DNA condensation and permitted the gene transfection into mammal’s cells [108,109]. Doxorubicin blended with copolymer poly (ethylene glycol)-poly (aspartame-hydrazine-doxorubicin) [(PEG-p (Asp-Hid-Dox)] produced polymeric micelles that are pH sensitive. This experimented formulation released the drug when pH decreased to a value less than 6 but retention of drug and the genes at a physiological pH was observed.

Glucose-responsive polymers for insulin delivery/biosensor:

Development of an insulin delivery system/technique for the treatment of diabetic patients is a popular application of pH-sensitive polymers [11, 126]. Unlike other drugs, what makes insulin delivery more difficult is the delivery of an accurate amount at the exact time of need. The enzyme glucose oxidase was studied and the pH-responsive polymers that form a covalent bond with the enzyme were developed as a pharmaceutical system for the delivery of insulin [108, 127]. The mechanism that triggers the release of insulin in this pharmaceutical system goes like this: Change in pH caused by the formation of glucuronic acid due to oxidation of glucose by glucose oxidase, makes the pH-sensitive hydrogel change its volume, expanding and releasing of insulin. It is done by using the pH-sensitive polycationic polymers like poly (2-diethylaminoethyl methacrylate) (PDEAEMA) to enhance the membrane’s permeability, facilitate the insulin delivery as a result of a decrease in pH value of the medium [108, 128]. Ionization of the polymer in an acidic environment is responsible for this increment in permeability.

Insulin-releasing beads were prepared using polymers that are sensitive to both pH as well as temperature. An example of such is P (NIPAA-co-BMA-co-AA) prepared by mounting it in an aqueous solution of appropriate pH [11, 129]. The beads were insoluble at acidic pH and hence the stomach experienced no drug release. Unlike in acidic pH, they low molecular weight hydrophilic polymer beads revealed a hump-like profile at normal body temperature and pH 7.4, consequently, dissolving in a 2 hour duration (bead dissolution – controlled release mechanism) whereas the macromolecular polymeric beads of hydrophilic nature expand and delivered insulin sustainably for the duration of 8 hours. Addition of an intermediate step in which an analyte gets transformed into pH fluctuation substance can prolong the applicability of pH-sensitive hydrogel for the sensor like in the hydrogel-based PCO₂ sensor. In this pharmaceutical system, the release of CO₂gas forming carbonic acid in water. Due to this, there is a changing pH of the system and consequently in the volume of pH-sensitive HGs [11, 130].

Takamaya K., Morishita M., Nagai T., Lowman A.M., collectively described the modified insulin delivery using pH-responsive polymers [108, 131]. These authors worked on the development of insulin delivery and were successful in formulating microparticle P( MMA- g – EG) with poly (methacrylic acid) –g poly( ethylene glycol) which in acidic support the delay of insulin delivery through the gut whereas the delivery is rapid in neutral or alkaline environment AA ( ACRYLIC ACID) is another pH-responsive polymer employed in insulin delivery. Another formulation was by Foss et.al. ( 2004), in which the group developed nanoparticles of polyacrylic acid (AA) – g- PEG for delivery of insulin by oral means and concluded that AA becomes hydrophilic due to ionization at pH above the pKa of 4.5 [108, 132].

Additional applications:

Chromatographic studies:

Apart from drug delivery, pH-responsive polymers can be applied to the purification and separation technology. Chromatographic systems are used to separate various molecules like peptides, enzymes, proteins, etc. The change in environmental pH causes either protonation or deprotonation of pH-responsive polymers because they contain alkaline or acidic groups such as amine and carboxylic acids attached to the hydrophobic backbone. The protein separation by pH-sensitive polymers is via electrostatic interactions because these polymers can readily interact with proteins that are oppositely charged by complexation consequently resulting in precipitation. Recovery of the precipitated proteins is possible by changing the pH of the medium. Both acidic and basic polymers have been used in preparing pH-responsive chromatographic materials. The acidic polymers used are PMAAc, PAMPS, PAAc, PLL, etc., and the basic polymers used are PDMA, PVI, PDMAPAm, P4VP, PANMP, etc [10, 133].

Future progression/ perspectives:

The use of biomaterials in upcoming future focus towards the improvement and clinical utilization of smart materials allowing better control over occurrence in a post-implantation. Modification pH, ionic strength or other molecular interaction, the material can be controlled by a host cell. The utilization of supramolecular assemblies of sensitive polymers (example, cross-linking or shell) is done to achieve structural stability for a longer time. Development and incorporation of detection design having high sensitive and particular responses into sensitive matrix polymers, aimed at detecting and differentiating minimal fluctuations in the concentration of glucose and bioactive molecules along with pH, the temperature should be further developed. The improvement of pH-sensitive polymers is primarily focused on the system able to select and identify various analyses at the same time. Incorporation of detecting and identifying quality in medical device remains a challenge to consolidate material response which guarantees that these ideal smart materials achieve their application potential both in vitro and in vivo. The thorough investigation of in vivo uses are being explored, with promising work towards treatment therapy and targeted drug delivery system. The consolidation of distinctive properties of multi- responsive polymers, will give rise to new methodologies, augmenting both efficacy specificity of cell focusing, cell responsiveness, and drug delivery. The achievement of a specific application, appropriate copolymerization, cross-linking and ligand connection the characteristics of smart materials should be tailored. The production of smart materials by ideal techniques are so far giving a new strategy for delivery of the drug, neuronal, tissue engineering for regenerative medicines. Before their appropriate application for clinical treatment, the future trend should be centered on optimizing the exact necessity of this material.

CONCLUSION:

Different techniques in the area of pH-sensitive polymers and their uses as a drug delivery agent, gene carrier, and biosensor has been adopted for synthesis acid/alkaline responsive polymers. Acid-sensitive drugs and colon drug delivery products can be prevented and improve their pharmacokinetic/ pharmacodynamics properties by utilization of smart polymers. In the area of gene carriers, pH-responsive polymers system properties and application has been used as one of the promising application. Looking at applied perspectives viewpoints, the pH-responsive system has been thoroughly studied, such system can be synthesized via controlled polymerization or Free radical polymerization techniques. All the above techniques and application depicts promising results giving an area for development in the upcoming future. pH-sensitive polymers have many pros as modified and controlled release pharmaceutical dosage forms, reducing toxicity, bizarre reaction and side effects by releasing and distributing the drugs at the appropriate site. This type of pharmaceutical system precisely reduce the therapeutic dose and improve the patient compliance. Such a system has more advantages in addition to the above that is easy production, cost-effective which is an inspiration for a pharmaceutical company.

Abbreviations:

MAA Methacrylic acid

MePEGA Poly(methoxypolyethylene glycol acrylamide

P4VP Poly(4-vinylpyridine)

PAA poly acrylic acid

PAAPBA Poly(3-acrylamidophenylboronic acid)

PDEA Poly[(2-diethylamino)ethyl methacrylate]

PDMA Poly[(2-dimethylaminoethyl) methacrylate]

PDMAEMA N, N-dimethylaminoethyl methacrylate

PDPA Poly(2-diisoprophylamino)ethyl methacrylate

PEAAc Poly(ethyl acrylic acid)

PEG Polyethylene glycol

PEGDG Polyethylene glycol diglycidylether

PEO Polyethylene oxide

PEPyM Poly(N-ethylpyrrolidine methacrylate)

PG2MA Poly(glycerol monomethacrylate)

PGMA Poly(glycidyl methacrylate)

PHPMA Poly[N-(2-hydroxypropyl)methacrylate]

PIMMA Poly[2-(isobutyramido)-3-methylbutyl methacrylate]

PLA Polylactide

PLGA Poly(L-glutamic acid)

PLL Poly(L-lysine)

PMAAc Poly(methacrylic acid)

PMEMA Poly(2-N-morpholinoethyl)methacrylate

PMEO2MA Poly[2-(2-methoxyethoxy)ethyl methacrylate]

PMPS Poly[3-(trimethoxysilyl)propyl methacrylate]

PNIPAm Poly(N-isopropylacrylamide)

PPAA Poly(propylacrylic acid)

PPDPMA Poly[N-2(3-pentadecylphenoxy)ethyl methacrylamide]

PSP Poly(spiropyan-functionalized

PTEGMA Poly[2-(2-(2-methoxyethoxy)ethoxy)ethyl methacrylate]

PVA Polyvinyl alcohol

PVI Poly(N-vinylimidazole)

PVPBA Poly(vinylphenyl boronic acid)

PVSA Poly(vinylsulfonic acid)

RPHA Reducible poly(β-hydroxy amine)s

QDMA Quaternized DMA

βDMA Sulfobetaine DMA

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Received on 24.09.2018 Modified on 21.10.2018

Research J. Pharm. and Tech 2019; 12(2):944-958.

DOI: 10.5958/0974-360X.2019.00159.8

Physiological fluid	Volume (l)	pH	Sodium ion concentration (mEq/l)	Potassium ion concentration (mEq/l)	Chlorine ion concentration (mEq /l)	Bicarbonate Ion concentration (mEq/l)
Intracellular fluid	30	-	10	160	115	30
Interstitial fluid	10	-	150	5	110	30
Large intestine fluid	1.0-1.5	5.5-7.0	130	10	95	20
Small intestine Fluid	1.5	7.5-8.0	120	5	110	35
Saliva	1.5	6.0-7.0	30	20	30	15
Gastric Fluid	2.5	1.0-3.5 fasting	50 (H+,90)	10	110	0
Bile	0.5	7.8	140	5	105	40
Pancreatic fluid	0.7	8.0-8.3	140	5	60	90
plasma	3	7.4	140	5	100	30

Responsive to	Polymers	Type	Reference
Glucose, pH, and thermo	PDMA-co- PAAPBA	Microgel	42
Light, pH, and thermo	PDMA-co-PSP	Micelle	43,44
Glucose and pH	PVPBA-co-PDMAEA	Nanogel	45
Glucose and light	MePEG-b-(PNBA-co-PAAPBA	Micelle	46
pH and magnetic	PMAAc	Microgel	47
pH and electric	PAAc-co-PVSA	Microgel	48
pH and reduction	PEO-b-(PMAAc-g-Hyd)	Micelle	49
	RPHA-g-coumarin	Micelle	50
Thermo and enzyme	PPDPMA-co-PTEGMA	Micelle	51
pH and thermo	PVI-co-PIMMA	Coplymer	52
	PNIPAm-co-PDMA	Nanogel	53
	PEPyM	Macrogel	54
	PNIPAm-b-PAAc	Micelle	55
	PEG-b-P4VP-b-PNIPAm	Micelle	56
	PNIPAm-b-PDEA	Micelle	57
	PDPA-b-PDMA-b-PDPA	Micelle	58
	PDMA-b-PAAc	Micelle	59
	PDMA-b-PDEA	Micelle	60
	PDMA-b-PDPA	Micelle	61
	[PMEO₂MA-b-(PDEA-co-PTPHMA)]	Micelle	62
	PEO-b-[PGMA-g-(PDEA)(PMEO₂MA)]	Micelle	63
	PMAAc-co-PNIPAm	Yolk/Shell	64
	PDMA-b-PMPS	Micelle	65
	PNIPAm-b-PLGA	Micelle	66
pH, thermo and salt	PDEMA	Microgel	67
	PDEA-b-PMEMA	Micelle	68
	PQDMA-b-PMEMA	Micelle	69
	PβDMA-b-PMEMA	Micelle	70