Role Of Polymers As Engineered Platform For

Pharmaceutical Dosage Forms

Mullaicharam Bhupathyraaj 1,*, Alka Ahuja 1, Nirmala Halligudi 1,*

1
*Professor, Department of Pharmaceutics, College of Pharmacy, National University of Science and Technology, Muscat, 130,
Oman
1
Professor, Department of Pharmaceutics, College of Pharmacy, National University of Science and Technology, Muscat, 130,
Oman
1
*Assistant Professor, Department of Pharmaceutical Chemistry, College of Pharmacy, National University of Science and
Technology, Muscat, 130, Oman

*Corresponding author: Mullaicharam Bhupathyraaj

Email: [email protected]
DOI: 10.47750/pnr.2022.13.S07.638

An engineered dosage form architecture is used in Pharmaceutical technology to formulate novel dosage forms with excellent
performance in terms of release and availability. Polymers are the main excipients in the design of dosage forms, irrespective of
the route of administration. They play many roles as a support vehicles. This review aims to provide brief information on the use
of Pharmaceutical polymers in sustained released dosage forms. Based on the literature review, they are classified into three
categories depending on their use. Polymers are used to modify the solubility and bioavailability of solid dosage forms, increase
the stability of liquid dosage forms, and modify the drug release kinetics in novel dosage forms. There are numerous advantages
of polymers acting as inert carriers to which a drug can be added in an active form for the continuous release of the drug over an
extended period.

Keywords: Sustained release: Polymers; Drug Delivery; Novel dosage forms

INTRODUCTION

An existing drug molecule can be converted into a novel form using a Novel Drug Delivery System approach. An
appropriately designed Novel Drug Delivery System can be a major advantage in solving the problems related to the
release of the drug at a specific site at a specific rate [1]. The necessity of drug delivery to the patients efficiently and
effectively and also to ensure that the side effects are minimized, has resulted in Pharma companies adopting the
development of new drug delivery systems using different types of polymers. Controlled and Novel Drug Delivery
which was only a dream or at best a possibility is now a reality. In-depth research has been carried out by the Pharma
institutions as well as other scientists in this particular area of drug research in the last 10-15 years [2, 3,4,5]. To
minimize drug degradation, prevent harmful side effects, and increase drug bio-availability, drug delivery systems are
designed through the integration of polymer science, pharmaceutics, bio-conjugate chemistry, and molecular biology.

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The huge variety of polymers to be had for pharmaceutical use, their low reactivity in the direction of pills and different
method ingredients, and their secure nature have authorized large use of polymers to enhance production tactics or for
the method of pharmaceutical dosage bureaucracy for diverse management routes [6,7].

Moreover, the practice of the latest polymeric substances via way of means of the synthesis of the latest polymers with
precise homes or via way of means of the amendment of to-be-had herbal or artificial polymers gives the formulator
an extensive variety of programs to optimize the delivery of drugs for every unique case.

2. Classification of the polymers

2.1. Based on the origin

2.1.1. Natural polymers

Natural polymers are substances that are obtained from natural sources like plant and animal sources. In the
formulation of Pharma products, the natural polymers used are polymer polysaccharides, gummy exudates, enzymes,
proteins, and muscle fibers. The unique uses of plant-derived polymers like chitosan, carrageenan, isapghula, acacia,
gelatin, agar, shellac, and guar gum in pharmaceutical formulations consist of their use with-inside the manufacture
of stable monolithic matrix systems, implants, films, beads, microparticles, nanoparticles, the inhalable and injectable
device in addition to viscous liquid formulations[9,10]. Examples include Proteins-collagen, keratin, albumin,
Carbohydrates-starch, cellulose, glycogen, etc. Matrix tablets, pellets, and beads are examples of a few Drug de-livery
systems where they are used.

Collagen: A major natural protein component like Collagen is fabricated from glycine-proline (hydroxy) and is found
in animals. It meets a variety of drug delivery system characteristics, including strong biocompatibility, low
antigenicity, and degradability after implantation which is widely employed in pharmaceutical formulations [12, 15].
One of the first natural polymers to be employed as a promising matrix for drug delivery and tissue engineering was
collagen gels [11, 13]. Because it provides greater storage stability, a longer drug release rate, and increased
therapeutic efficacy, a combination of liposomes and collagen-based technologies has been applied.

2.1.2. Synthetic polymer

Synthetic polymers are chemical compounds made in an industrial setting that is made up of several molecules bound
together by covalent bonds. [16, 18]. A lot of synthetic polymers are available with variations in the main chain as
well as the side chain. Polythene and polystyrene are the generally used synthetic polymers. e.g. Polyester,
polyanhydrides, polyamides, polyglycolic acid etc.[17,19].

Polyglycolic acid (PGA) is made via ring-opening polymerization of glycolide, a cyclic diester of glycolic acid. It's a
crystalline strong, rigid polymer with a melting point of.225 °C and a glass transition temperature of 36 °C. PGA was
first introduced in 1970 as the first synthetic absorbable suture under the brand name Dexon TM. It has exceptional
fiber-forming properties. Because it cannot be formed into films, rods, capsules, or micro-spheres using solvent or
melt processes, PGA's limited solubility and high melting temperature limit its usage in drug delivery applications.
[20, 21]. They are used in insulin re-lease devices, films, micro-particles, rods, and particulate formulations.

2.2. Based on Bio-stability

2.2.1. Biodegradable Polymers

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The polymer that is degraded by the action of biologically resulting bacteria and fungi is known as a biodegradable
polymer. The biodegradable polymers are degraded in the body to biologically inert and compatible molecules and
are highly desirable. Examples include polyester, proteins, carbohydrates, etc [22, 24].

Alginates: A naturally occurring linear polysaccharide like alginate is widely used in drug delivery because of its
many unique properties, including biocompatibility, biodegradability, non-immunogenicity, water-solubility, low
cost, low toxicity, gelling ability, stabilizing properties, and high viscosity in aqueous solutions [23,25,26]. The cross-
linking procedure is carried out at physiological pH and room temperature. Alginate-based systems have been
effectively used as a matrix for encapsulating stem cells and releasing proteins, genes, and medicines under controlled
conditions [28]. Alginate-based microcapsules and Hydrogel are just a few examples of how they're used in drug
delivery.

2.2.2. Non-biodegradable polymers

These polymers are used in pharmaceutical formulations to increase the therapeutic efficacy of drugs [30,34]. They
are used in drug delivery systems and tissue engineering. The non-biodegradable polymers used in pharmaceutical
formulations include Ethyl-cellulose, HPMC, acrylic polymer, polyethylene glycol, etc.

Polyethylene glycol

The interaction of ethylene oxide with water, ethylene glycol, or ethylene glycol oligomers produces polyethylene
glycol (PEG). Because it is soluble in water and has low inherent toxicity, PEG is ideal for biological applications
[27]. When coupled with hydro-phobic medicines or carriers, PEG's high hydrophilic nature increases its solubility.
It im-proves the medication's physical and chemical stability, as well as prevents drug aggregation in vivo and during
storage [21,29]. PEG aids in the reduction of red blood cell aggregation and increases the blood compatibility of PEG
copolymers used in cardiovascular devices like stents [34, 35].

3. Physical properties

Physical properties that contribute to the rate of biodegradation of polymer.

3.1. Water permeability and water solubility

The rate of hydrolysis and whether bulk or surface hydrolytic breakdown happens will be determined by the polymer's
free volume and hydrophilicity. [27].

3.2. The crystallinity of the polymer

Only the amorphous phase of the polymer is accessible to permeate (i.e. Water drug) and to enzymatic attack [15,19].

3.3. Glass-transition temperature

The nature of the polymer viz., rubbery or glassy is observed in its molecular chain mobility and permeability. Chain
mobility appears to be an important factor in determining the susceptibility to enzymatic attack [15].

3.4. Physical dimensions

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Size and surface-to-volume ratio appear to become significant in the advanced stages of biodegradation, when
phagocytosis may come into play.

4. Need for biodegradable polymers

Non-biodegradable polymers are high-priced and invasive because they require surgical elimination after the crowning
glory of drug release and can reason tissue toxicity if retained for a longer time. The diffusion-managed launch is a
splendid means of achieving managed drug transport, however, it's far constrained with the aid of the polymer
permeability, the characteristics of a drug, and its diffusion coefficient [3, 7]. Biodegradable polymers do not want a
second surgical treatment for the elimination of the polymer because it undergoes auto-biodegradation.

5. Characterization of polymers

In general, polymers used for biomedical and pharmaceutical applications need to be characterized to determine their
molecular weight, composition, and thermal properties. All of these attributes have an impact on the properties of the
final product. The morphology and mechanical properties, molecular structure, and molecular mass are ascertained by
employing the characterization technique [21]. Cross-linked polymers have infinite molecular weight and the
molecular weight of polymers ranges from a few hundred to several million grams per mole. Polymers obtained from
chemical synthesis form a family of macromolecular species which are characterized by a mean molecular weight
with a certain distribution termed polymolecularity. This effect adds heterogeneity to chemically synthesized
copolymers, and the only way to appreciate this effect is to analyze the com-position of the polymers at low conversion
degrees during polymer synthesis [17, 25, 26].

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Figure 1. Structures of biodegradable and biocompatible polymers.

Some of the newly developed/used polymers are classified into the following categories:

6. Smart polymers

They are very efficient polymers. The environment in which they inhabit may bring about a corresponding change in
them. There may be a significant change in the properties of the polymer due to a minor change in the environment
[28]. A change in the pH may bring about a variation in their water retention properties, adhesiveness, and con-
formation. Hydrogels and other materials are manufactured using smart polymers. Thus, smart polymers are well-
suited for usage in drug formulations. The cross-linking of pH-sensitive smart polymeric chains produces some smart
polymers. The behavior of smart polymers is determined by the polymer composition, the nature of the ionizable
groups, the cross-linking density, and the hydrophilicity of the polymer backbone. The permeability of the solute is
inversely proportional to the crosslinking density; the higher the crosslinking density, the lower the permeability [29].
Sustained-release gels are developed by the coprecipitation of Alginate gel beads with a biologically active agent. The
main advantage achieved is that of high loading of drugs while achieving better protein stability. LCST is a polymer,

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which has been tested in controlled drug delivery matrices [33]. The temperature sensitivity is maintained due to the
Co-polymerization of the NIPAAm with alkyl methacrylates as it increases its mechanical strength. The transportation
of the bioactive molecules out of the polymers is reduced due to the surrounding of the LCST with a thick layer of
poly NIPAAm polymer.

7. Polymers in tissue engineering

A wide range of natural origin polymers with special attention on proteins and poly-saccharides might be probably
beneficial as carrier structures for lively bio-molecules or as mobile providers with utility in the tissue engineering
area targeting several biological tissues [32,35].

8. Manufacturing/particle engineering design of polymeric microparticles and

nanopar-ticles

8.1. Double-Emulsion Evaporation Methods

Methylene chloride is the commonly used solvent for the dissolution of both the drug and biodegradable polymer with
the use of the emulsion/solvent evaporation technique. It results in the formation of o/w emulsion which is an organic
oil phase emulsified in an aqueous phase. The evaporation method is used for the removal of volatile solvents. Butyl
acetate, ethyl acetate, ethyl formate, or methylene ketone can be substituted for methylene chloride in medications
that do not have a high solubility in them [10,26]. Adding a cosolvent to methylene chloride is another possibility.
Hydrophilic peptides or proteins are either disseminated in an organic polymer solution or preferred processed in an
aqueous water-in-oil (w/o) emulsion solution, resulting in a w/o or w/o/w emulsion system. Due to a flux of
pharmaceuticals from the dispersed phase to the larger volume of the continuous phase during the manufacturing
process, o/w or w/o/w techniques are projected to result in low encapsulation efficiencies. [28]. Denaturation takes
place in the proteins that are encapsulated by w/o or w/o/w techniques into particles thereby, resulting in a loss of
biological activity, aggregation, oxidation, and cleavage, especially at the aqueous phase-solvent interface. It is
recommended that stabilizers and surfactants should be used during the primary emulsion phase so that the protein
integrity is improved.

Figure 2. Double-Emulsion Evaporation Methods [26].

8.2. Supercritical Fluid (SCF) Technology

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When substances are heated over their critical point, they become supercritical fluids (SCF), which have the flow
characteristics of gas and the dissolving characteristics of a liquid. Supercritical fluids' solvent power is influenced by
temperature, density, and pressure. There are numerous excellent evaluations on this cutting-edge particle engineering
design technique, which has found increasing utility in innovative delivery systems for a variety of routes of
administration, including non-invasive pulmonary delivery via pharmaceutical inhalation aerosols. [8]

In the Supercritical fluid, the drug and matrix may be dissolved and then formed into particles using the rapid
expansion from gas-saturated solution (PGSS) or supercritical solution (RESS) processes [28].

The RESS method, which produces fine particles by employing supercritical fluid as a solvent, consists of two
steps:

1. Adding the solute to a supercritical fluid and dissolving it.

2. Rapid supersaturation causes the solute to form micro-particles.

CO2 is an ideal solvent for several chemical and industrial processes since it is affordable, abundant, non-toxic, and
has a relatively accessible critical point, i.e., Tc = 304.2 K and Pc = 7.37 MPa. A supercritical fluid or dense gas is
employed as a solute in the PGSS process. Because CO2 has no polarity, it is difficult to dissolve polar or large
molecular-weight compounds like proteins. In the PGSS process, however, CO2's propensity to permeate into organic
substances allows composite particles to form.

CO2 lowers a compound's melting point and viscosity as its concentration rises [35, 36]. As a result, the compounds
melt in compressed gas, and the concentration of a gas in a molten solute rises with increasing pressure, generating a
saturated solution. Due to the escape of gas from the condensed phase, the formation of composite microcapsules
occurs when this solution is rapidly depressurized through a nozzle.

Figure 3. Supercritical Fluid (SCF) Technology [35, 36].

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8.3. Supercritical Anti-Solvent Method

Because of its readily accessible critical point, availability, and low toxicity, CO 2 is the most commonly employed
supercritical fluid in medicinal applications. The anti-solvent approach, in addition to RESS and PGSS, uses CO2 as
an anti-solvent for particle synthesis. Anti-solvent methods take advantage of supercritical fluids' high miscibility with
organic solvents that have high dissolving power for the compound. GAS/SAS (supercritical anti-solvent), PCA
(precipitation with compressed supercritical fluid), ASES (aerosol solvent extraction system), and SEDS (solution-
enhanced dispersion by super-critical fluids) are some of the techniques[36]. The supercritical anti-solvent method
(GAS/SAS) is based on the addition of a second fluid as an anti-solvent, which causes a rapid drop in the solubilization
power of a solvent.

The anti-solvent expands the organic solution, causing the supersaturation-inducing solute to dissolve. To remove the
residual solvent, the precipitated particles are rinsed with an anti-solvent. Temperature, pressure, and composition can
all influence particle size. When compared to the one-way mass transfer of CO2 into the organic phase in the GAS
process, the PCA process involves a two-way mass transfer. CO2 diffuses into the organic phase, and the organic
solvent diffuses into the CO2. In the ASES process, the medication and polymer are dissolved or dispersed in an
organic solvent, which is normally soluble in supercritical CO 2, and then extracted, resulting in the creation of solid
micro-particles.

The mass transfer of the supercritical fluid into the sprayed droplet and the rate of solvent transfer into the supercritical
phase are credited with particle formation in the SEDS process [37]. Smaller particle size distribution and reduced
agglomeration are the outcomes of high mass transfer.

Figure 4. Supercritical Anti solvent Method [37].

8.4. Spray Drying Particle Engineering Design

Spray drying is widely employed in the efficient design and manufacture of food and pharmaceutical particles,
particularly particles for use in the formulation of inhalation aerosols. There are four steps to spray drying:

1. Conversion of feed solution into fine droplets in a spray through an atomization process

2. Usage of intimate flow and mixing for carrying out Spray-air contact;

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3. Drying of sprayed droplets at elevated temperatures; and

4. Separation of Dried particles from the air.

The operating parameters of the spray drying process, such as atomization pressure, feed rate, airflow, intake
temperature, output temperature, and the size of the nozzle orifice, must all be regulated to control the various particle
characteristics. Bigger particle size is produced by a smaller nozzle orifice, faster atomization airflow, and a low feed
concentration [12,35, 37]. Spray-freeze drying uses a two-fluid or ultrasonic nozzle to atomize an aqueous drug
solution into a spray chamber filled with a cryogenic liquid, such as liquid nitrogen, or a halocarbon refrigerant, such
as chlorofluorocarbon or hydrofluorocarbon. Due to the fast heat-transfer rate, the liquid droplets freeze quickly when
they come into touch with the cryogenic medium. The collected contents are lyophilized when the spraying procedure
is complete, and the frozen solvent is removed by vacuum or air freeze-drying. The mass flow ratio of atomized
nitrogen to liquid feed, which has the greatest influence on particle size, should be increased to achieve a lower particle
size. Spray freeze-drying can be used to make micro and nanoparticles.

Figure 5. Spray Drying Particle Engineering Design [35,37].

9. Significance of polymers

High immunogenicity-related polymers, make them unsuitable for long-term use. Non-biodegradable polymers must
be surgically removed after releasing the medication at the desired spot. Safety, efficacy, hydrophilicity, absence of
immunogenicity, biological inactivity, sufficient pharmacokinetics, and the presence of functional groups for covalent
conjugation of drugs, targeting moieties, or formation of co-polymer are some of the characteristics that make the
polymer a potential candidate for drug delivery [6,8,31,33].

The polymer, an inert provider to which a drug may be conjugated has multiple blessings, as example, the polymer
improves the pharmacokinetics and pharmacodynamics properties of biopharmaceuticals thru diverse ways, consisting
of, increasing the plasma 1/2-existence, decreasing the immunogenicity, boosting the steadiness of bio-
pharmaceuticals, improving the solubility of low molecular weight capsules, and the ability for focused drug
delivery.[8,14]Several diseases, such as cancer, ischemia, diabetes, hepatitis B and C, and rheumatoid arthritis have
been targeted by the polymer conjugates.

10. Conclusions

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The development of drug delivery carriers based on natural and synthetic polymers is a rapidly emerging field. It takes
benefit of the outstanding delivery mechanism that has been employed by selective targeting and prolonged circulation
by pathogens and mammalian cells by the deception of the immune systems. Polymeric drug delivery can likely be
solved with biomimetic and bio-inspired systems as the bright future. The use of bio-compatible polymers ensures
better control of the toxicity of the samples, which leads to safer, more reliable delivery of drugs. Polymeric materials
are needed to develop therapeutics at the nano-scale with new and improved features to address unresolved medical
needs as well as to enable personalized medicine. It is difficult to maintain the integrity of natural and synthetic
polymers with cells in a body due to the micro-processes that are required for the development of such carriers, such
as genetic engineering or in vivo treatments. Recent advances in the synthesis of novel biomaterials and understanding
of biological systems have helped bridge the gap between synthetic and biological systems. Shortly, the integration of
perspectives from synthetic and biological fields will help us develop new approaches for designing polymeric drug
delivery systems.

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