INTRODUCTION
1. DEFINATIONS
Microbeads are synthetic polymer particles that, at the time of their manufacture, are greater
than 0.1 µm and less than or equal to 5 mm in size, which can vary in chemical composition,
size, shape, density, and function. Microbeads are manufactured for specific purposes,
including for use in personal care products (such as scrubs, bath products, facial cleaners,
toothpastes). They may also be used in other consumer uses including cleaning products and
printer toners and in industrial products such as abrasive media (e.g., plastic blasting), industry
(e.g., oil and gas exploration, textile printing, and automotive molding), other plastic products
(anti-slip, anti-blocking applications) and medical applications.
Microbeads from ‘down the drain’ products will likely be released into the aquatic environment
after wastewater treatment. Studies have shown that microplastics, including microbeads, are
present in the environment and that they can reside in the environment for a long time.
Microbeads have been shown to elicit both short and long-term effects in laboratory organisms.
Microbeads are added as an exfoliating agent to cosmetics and personal care products, like
soap and toothpastes. In biomedical and health science research microbeads are used in fluid
visualization, fluid flow analysis, and microscopy techniques. Sphericity and particle size
uniformity create a ball bearing effect in creams and lotions, resulting in a silky texture.
Smoothners and roundness of microbeads provides lubrication.
In recent years extensive efforts are being made in various
pharmaceutical research laboratories for the development of novel and targeted drug
delivery system with an aim of improved patient convenience, better therapeutic efficacy,
less side effects, reduced dosage regimen, targeted drug delivery with less toxicity for
the treatment of cancer and other serious infective diseases. Conventional oral drug
delivery administration does not usually provide rate controlled release or target
specificity. In many cases conventional drug delivery provides sharp increase of drug
concentration of potentially toxic levels, drug concentration eventually decreases until re-
administration.
Today new methods of drug delivery are possible, desired drug release can be provided
by rate controlling membranes or by implanted bio degradable polymers containing
dispersed medications. [1,2] Controlled release systems include any drug delivery
system that releases the drug over an extended period of time. If the system is
successful in maintaining a constant drug level in the blood or target tissue, it is
considered as controlled release system. If it is unsuccessful in this but only extends
the duration of actions, it is considered as prolonged release system. Oral route is the
most convenient and common mode of administration of controlled release system. Oral
controlled release system include coated pellets, matrix tablets, microcapsules, mixed release
granules, poorly soluble drug a complexes, ion exchange resins, complexes, osmotic pumps
etc.,
Micro encapsulation is at present most common and rapidly expanding technology for
controlled drug delivery system."Microencapsulation is process by which thin coating can
be applied reproducibly to small particles of solids or droplets of liquid dispersions or
even gases are encapsulated into micro sonic particles".
Particle size range dimensionally from 1 µm to 1000 µm . Microspheres may assume
various shapes as globules, spherical, kidney shaped, rice grains like flocculate and
massive wall may contain one or many substances. Contents of the capsules are contained
within wall until released by some means that serve to break, crush, melt, dissolve,
rupture or remove the shell or the internal phase caused to diffuse out through the
capsule wall. [3-6]
Ionotropic Gelation method is used for preparation of beads by exchange of ions like Na+ or
Ca++ in this process Hydrogels (or) wet gels can be formulated.
Ionotropic gelation is based on the ability of polyelectrolytes to cross link in the presence of
counter ions to form hydrogels. Since, the use of alginates, gellan gum, chitosan, and
carboxymethyl cellulose for the encapsulation of drug and even cells, ionotropic gelation
technique has been widely used for this purpose [7] The natural polyelectrolytes inspite, having
a property of coating on the drug core and acts as release rate retardants contains certain anions
on their chemical structure. These anions forms meshwork structure by combining with the
polyvalent cations and induce gelation by binding mainly to the anion blocks. The hydrogel
beads are produced by dropping a drug-loaded polymeric solution into the aqueous solution of
polyvalent cations. The cations diffuses into the drug-loaded polymeric drops, forming a three
dimensional lattice of ionically crossed linked moiety. Biomolecules can also be loaded into
these hydrogel beads under mild conditions to retain their three dimensional structure.
Alginate is a non-toxic, biodegradable, naturally occurring polysaccharide obtained from
marine brown algae, certain species of bacteria. Sodium alginate is a sodium salt of alginic acid
a natural polysaccharide and a linear polymer composed of 1,4-linked β-D-Mannuronic acid
(M) and α-D- gluronic acid (G) residues in varying proportions and arrangements. The
homopolymer regions composed of M-blocks and G-blocks are interspersed with M G
heteropolymeric regions known as “egg box junction” [8, 9] .
Microplastics are organized according to their source, i.e. whether they are manufactured on
the micrometer size or are the result of breakdown processes discussed above (such as
weathering, photodegradation, etc.) (GESAMP, 2015).
For the purposes of this summary:
• Microbeads are defined as synthetic polymer particles that, at the time of their manufacture,
are greater than 0.1 µm and less than or equal to 5 mm in size. This includes different forms of
particles including solid, hollow, amorphous, solubilized, etc. • Secondary microplastics are
synthetic polymer particles that originate from the breakdown of larger plastic items (Andrady,
2011). • Microplastics include microbeads and secondary microplastics. • A personal care
product is defined as a substance or mixture of substances which is generally recognized by
the public for use in daily cleansing or grooming. Depending on how the product is represented
for sale and its composition, personal care products may fall into one of three regulatory
categories in Canada: cosmetics, drugs or natural health products.
2. Substance Identity, Properties and Uses
2.1 Substance Identity
Microbeads are synthetic polymer particles manufactured to be in the size range of >0.1 µm –
≤5 mm for a specific purpose and application. They can be composed of a variety of synthetic
polymers depending on the required functionality. Table 1 lists the function of typical
polymeric particulates found in personal care and cosmetic products (Leslie, 2014). In the case
of microbeads, the most common polymers used are polyethylene, poly(methyl methacrylate),
polytetrafluoroethylene, polypropylene, Nylon, and polyethylene terephthalate (Norwegian
Environment Agency, 2014). Typical polymer forming reactions used to synthesize
microbeads are based on the desired particle size (Jinhua & Guangyuan, 2014) and include
emulsion polymerization (Chern, 2006; Asua, 2004), suspension polymerization (Brooks et al.,
2010; Dowding & Vincent, 2000), and dispersion polymerization (He et al.,2011; DeSimone
et al., 1994; Li & Armes, 2010). In addition, microbeads also contain residual chemicals as a
result of their synthesis, such as unreacted monomers/reactants, petroleum-based chemicals,
etc. These residual chemicals are different than environmental pollutants which adsorb onto
the particle during its various life-cycle stages, especially within the aquatic environment (Mato
et al., 2001; Teuten et al., 2007).
2.2 Properties
Microbeads can vary in size, shape and density based on the chemical composition and method
of synthesis (Napper & Thompson, 2015 in press). As can be seen from Table 2 (Hidalgo-Ruz
et al., 2012), polymer particles (which include microbeads) can range in polymer densities from
0.9-2.10 g/cm3 (density of water at 25°C is approximately 1 g/cm3). In addition to polymer
densities, the density of the
entire particle will also be a function of other chemicals added during its manufacture (e.g.,
additives, fillers, etc). This variation in densities means that some synthetic polymer particles
(including microbeads) will float on water surfaces and others may be present in the water
column or settle to the sediments. Once in the environment, this behaviour will change
depending on the aggregation/dis- aggregation and agglomeration/dis-agglomeration
behaviour as the microbeads interact with environmental media, e.g., humic/fulvic acids.
Moreover, synthetic particles (e.g., plastics) may become fouled by organisms and as a
consequence, particles that initially floated may eventually sink to the sea bed. For example,
substantial quantities of microplastics have been reported in deep sea sediments (Woodall et
al., 2014).
2.3 Uses
Globally, microbeads have been found to have use in personal care products, other consumer
applications, and various industrial applications.
Based on information presented in scientific literature considering personal care products,
microbeads have been found in scrubs/peelings, shower/bath products, facial cleaners, creams,
deodorants, make- up foundations, nail polishes, eye colours, shaving creams, bubble baths,
hair colourings, insect repellants, toothpaste, eye shadows, blush powders, hairsprays, liquid
makeups, mascaras, baby products, lotions, and sunscreens. Microbeads may also be found in
other consumer uses/products including cleaning products and printer toner (Norwegian
Environment Agency, 2014). Some products contain substantial quantities of microbeads. For
example, Napper and Thompson (2015, in press) quantified microbeads incorporated in
personal care products as exfoliants and showed that abundance varied considerably among
products (137,000 – 2,800,000 per 150ml bottle). Some products that are used on a daily basis
could result in release to household waste water of 94,500 microbead particles per application
(Napper & Thompson, 2015 in press).
In 2015, the Canadian Cosmetic, Toiletry, and Fragrance Association (CCTFA) voluntarily
surveyed its members and shared summarized information with the Government of Canada.
CCTFA information indicates that in Canada, microbeads were reported to be used in personal
care product categories of skin care (which include anti-aging creams, moisturizers, cleansers,
etc.), bath and body (which include bath/shower gels or soaps, lotions, talcs or balms, nail
polishes, etc.), and cosmetic-like products, which include fluoridated toothpastes, acne therapy,
etc. While the specific products were not reported, the total annual volumes of microbeads in
Canada by individual CCTFA members ranged from 30kg/year to 68,000 kg/year.
Microbeads are also used in industrial products such as abrasive media (e.g., plastic blasting at
shipyards, productions facilities such as garment and car parts), industry (e.g., oil and gas
exploration, textile printing, and automotive molding), other plastics products (e.g., anti-slip
and anti-blocking applications) and medical applications (biotechnology and biomedical
research) (Leslie, 2014; Norwegian Environment Agency, 2014).
formulating of new medicines. So, research continuously keeps on searching for new ways to
deliver drugs over a long period of time or for a well-
LITERATURE REVIEW (Minimum 10)
Tiwari Ritesh Kumar et al., 2013 studied that the design of effective and safe new drug
delivery systems has become an integral part for the development and controlled release
profile, to minimizing the loss of drug, to reduce the side effect. Synthetic polymer shows
various disadvantages, like higher in cost, non-biocompatible, toxic. Natural polymer sodium
alginate is used as the matrix because of its natural, biodegradability, low cost, simplicity, and
biocompatibility. Alginate is act as nontoxic when taken orally and also shows the protective
effect on the mucous membrane of upper gastro-intestinal tract. The gelation of anionic
polysaccharide sodium alginate, the primary polymer of natural origin, was achieved with
oppositely charged calcium ions and to form micro-beads. The technique employed to
preparation of micro-beads with sodium alginate by ionotropic gelation technique, cross-
linking, Emulsion gelation technique, spray drying, and simple and complex co-acervatio phase
separation method. This review focused on preparation, characterization of alginate micro-
beads, therapeutic application and their role in controlled or novel drug delivery systems6.
Umesh D. Shivhare studied that microparticulate drug delivery systems have various well-
known advantages over single unit dosage form. One of the most exploited techniques to
formulate microparticulate drug delivery is microencapsulation. Although it offers many
significant advantages it is only at the sake of some drawbacks. Some of important drawbacks
of these techniques include the use of more or less harsh conditions in the formulation process
which limits the many substances such as protein, enzyme and live cells etc. as core material
for encapsulation. Preparation of microbeads drug delivery system is one of the alternatives to
overcome above problem which involves neither use of harsh chemical nor elevated
temperature. The conventional techniques involve the use of- Ionotropic gelation method,
Emulsion gelation method, Polyelectrolyte complexation method. Majority of work has been
done on preparation of microbeads by ionotropic gelation method rather than other methods
owing to its ease of preparation for the treatment of various diseases it will be interesting in
assess the release pattern of the drug from microbeads using different preparation techniques.
Hence, the objectives of the present study is formulation and development of microbeads by
different techniques using the water soluble drug and comparing the drug release pattern of
prepared microbeads so as to obtain the ideal method among various techniques.
W. Zam studied that sodium alginate and combinations of sodium alginate- pectin were used
to study the effect on the loading efficiency and the radical scavenging activity of the
polyphenols extracted from pomegranate peels (Punica granatum). The results indicate that the
polyphenol content was less when the microbeads were prepared with a single type of polymer
in comparison of the microbeads prepared with two types of polymers. Also there was an
optimum ratio of these two polymers (2:1), which was responsible for the maximum
polyphenol content. The microencapsulated particles provided to polyphenols an effective
protection against the degradation phenomenon, whereas antioxidant activity remained
identical. In-vitro release studies indicated that 64.87% and 48.81% of polyphenols was
released in simulated gastric fluid from sodium alginate and sodium alginate-pectin microbeads
respectively. 88.37% and 70.48% of polyphenols was released in simulated intestinal fluid
from sodium alginate and sodium alginate-pectin microbeads respectively. The microcapsules
described in this study represent an interesting food additive for incorporation into functional
foods.
Kapoor D. studied that extended release formulations are becoming more popular day by day
for the delivery of non-steroidal anti-inflammatory drugs (NSAIDs) because of their ability to
maintain optimal and therapeutically effective drug levels for prolonged duration with the
reduction in dosing frequency and side effects associated with NSAIDs. Etodolac is a non-
steroidal anti-inflammatory drug. It is an inhibitor of cycloxygenase which belongs to the
pyranocarboxylic acid group, which is effective in treating fever, pain, and inflammation in the
body, which is degraded in the stomach. In the present study, a suitable particulate system of
Etodolac has been developed, by ionotropic gelation method for sustained release that would
result in prolonged clinical efficacy, reduced frequency of administration and lesser side
effects. Micro beads were fabricated with and without using guar gum as polymer and were
characterized for particle size and size distribution analysis, flow properties, loose surface
crystal study, entrapment efficiency, swelling ratio, percentage yield and drug content
uniformity and in-vitro drug release. It was found that the particle size distribution of both
formulations was varied within a narrow size range. Drug leaching (14.98 % ± 0.118) was more
with presence of guar gum. Entrapment efficiency was retarded with the presence of guar gum.
Swelling ratio (53.49 ± 1.874) advocated that guar gum incorporated microbeads swelled more
to behave as a matrix for controlled drug delivery. Establishment of highly viscous dispersion
with the incorporation of polymer led to high percentage yield (49.35% ± 01.230). Drug release
data was fitted to various kinetic models and indicated that the mechanism was according to
peppas model. The study discovered that the microbeads of Etodolac could be efficaciously
formulated by ionotropic gelation technique with sustained release characteristics.
• Smriti the present research work discusses the formulation and evaluation
of floating microbeads of ciprofloxacin HCL by emulsion gelation method.
The objective of this investigation is to develop a multi-unit gastro retentive
sustained release dosage form of a water soluble drug, Ciprofloxacin, from
a completely aqueous environment avoiding the use of any organic solvent.
A new emulsion gelation technique is used to prepare emulsion gel beads
using sodium alginate as the polymer. The gel beads containing is prepare
by gently mixing or homogenizing oil and water phase containing sodium
alginate which is then extruded in to calcium chloride solution. The effects
of factors like concentration of oil, curing time, drug: polymer ratio,
alginate: pectin ratio and curing agent on drug entrapment efficiency,
floating lag time, morphology and drug release are study. Minimizing the
curing time of beads leaded to enhanced drug entrapment efficiency. The
use of sodium alginate and combinations of sodium alginate and pectin are
used to study the effect on the sustaining property of the formed beads. It is
found that sodium alginate was not sufficient to sustain the drug release at
gastric pH. Instead of it, appropriate combination of alginate and pectin
could provide the sustain release of drug. The results show that these beads
can entrap even a water soluble drug as Ciprofloxacin in sufficient amount
and also can successfully deliver the drug in stomach for a prolong duration
of time. The Physical appearance and melting point of drug were found to
be concordant with that mentioned in USP, 29 and Clarke’s Analysis of
Drugs and Poisons, 2006 respectively which shows the purity of the sample.
IR spectrum of the drug sample was obtained by FT/IR. Its characteristic
absorption bands proved its identity.
• Anuranjita Kundu oral controlled drug delivery systems represent the most
popular form of sustained drug delivery systems for the obvious advantages
of oral route of drug administration. Such systems release the drug with
constant or variable release rates. The oral controlled release systems shows
a typical pattern of drug release in which the drug concentration is
maintained in the therapeutic window for a prolonged period of time
(sustained release), thereby ensuring sustained therapeutic action. They are
used as single dosage form. Present work involves preparation and
evaluation of sustained release of microspheres of norloxacin employing
sodium alginate as natural polymer. The technique employed for
microencapsulation of the drug is ionotropic gelation.
• B. Kasturibai studies to formulate Venlafaxine Hydrochloride loaded
microbeads of sodium alginate using gelatin and pectin as release modifiers
by Ionotropic Gellation Method. The microbeads were prepared by varying
the concentration of sodium alginate, gelatin and pectin. The drug – polymer
compatibility was studied by FTIR studies. No significant drug-polymer
interaction were observed in FTIR studies. The prepared microbeads were
evaluated mainly for the Sustained Release of the drug apart from the other
tests like swelling ratio, particle size, drug entrapment, SEM, in vitro release
study. Particle size distribution of the loaded formulations were measured
by an optical microscope and particle size of optimized beads was
determined by SEM. In vitro drug release profile of Venlafaxine
Hydrochloride microbeads was examined in 0.1N Hydrochloric acid for first
2 hrs followed by pH 7.4 phosphate buffer for 8 hrs. The formulated beads
had shown higher entrapment efficiency, drug loading, low particle size.
The formulation F6 released Venlafaxine Hydrochloride for longer duration
up to 10hrs.
• Sanjay Kumar Panda studies to prepare floating microbeads of Zidovudine
as model drug to achieve an extended retention in upper GIT which results
in enhanced absorption, thereby improves bioavailability and avoiding
multiple dosing for hospital acquired infections. In the present investigation,
microbeads were prepared by ion-gelation method using polymers like
sodium alginate, hydroxy propyl methyl cellulose (K100M), gas forming
agent like sodium bicarbonate, and curing agents such as calcium chloride
and Barium chloride solutions. Prepared microbeads were evaluated for
micromeritic property, particle size and morphology, in-vitro buoyancy
study, drug loading and encapsulation efficiency and in-vitro drug release
kinetic studies. All the formulations produced optimal flow properties as
represented in terms of compressibility. Result showed barium chloride
cross linked formulations showed the excellent flow ability as compared to
calcium chloride cross linked formulations. SEM study revealed irregular
surfaces with pores. The alginate floating microbeads were shown good
floating ability. The prepared microbeads exhibited prolonged drug release
for 12 hrs and remained buoyant up to 8 hrs. Barium chloride linked
microbeads showed better drug release of 91.78 percentage and drug content
of 87.14 percentages as compared to calcium chloride linked. Thus, it can
alternatively be used to avoid multiple dosing, thereby reducing the chance
of dose dumping.
• Nagakanyaka Devi Paladugu studies that flurbiprofen is a potent non-
steroidal anti-inflammatory drug that can be used for rheumatoid arthritis,
osteoarthritis, alkylosing spondylitis, tendinitis etc. Its shorter biological
half life (3 – 4.5 hrs) necessitates it to be administered in frequent doses of
50 – 100mg two to four times a day. The main objective of this study was
to develop suitable microparticulate system of Flurbiprofen for controlled
release delivery system by varying the sodium alginate, PEG 6000 and
HPMC concentrations. In the present work Flubriprofen microbeads were
formulated using sodium alginate by ionotropic gelation technique.
Prepared beads were evaluated for granulometric studies, micromeretic,
scanning electron microscopy, drug entrapment efficiency and in-vitro
dissolution studies etc. The prepared beads were free flowing and white in
colour. The drug loaded beads showed 87.5– 98.8 % drug entrapment,
which was found to increase with increase in sodium alginate, HPMC, PEG
6000 concentration. Scanning electron microscopy revealed that the beads
were almost spherical and rough in structure. The flow property of the all
the batches of prepared microbeads were estimated by angle of repose and
found to be in the range of 24050ˈ – 33020ˈ In vitro drug release study of
these microbeads indicated controlled release of Flurbiprofen, formulations
showed a release of 73.67-93.5% at the end of 10 h. Hence from the
observation of all results of the different batches fourth and fifth showed
controlled release action and improved drug availability. The release of
Flurbiprofen was found to be affected by concentration of polymers such
as sodium alginate, PEG 6000 and HPMC By the observation of accelerated
stability studies fourth and fifth batch formulations were found to be the best
formulations. From this study, it could be concluded that the spherical and
free flowing microbeads of Flurbiprofen could be successfully prepared by
ionotropic gelation technique with high entrapment efficiency.
• Hemalatha. K studies that metoclopramide hydrochloride is an antiemetic
and prokinetic agent used in the treatment of gastroparesis and
gastroesophageal reflux disease. The half life of metoclopramide
hydrochloride is 4- 6 hours. Metoclopramide hydrochloride microbeads
were prepared by ionotropic gelation method using sodium alginate in
combination with guargum and HPMC as drug release modifiers in various
proportions to overcome the drug related adverse effects. No significant
drug-polymer interactions were observed in FT-IR studies. The drug
entrapment efficiency increased progressively with increasing
concentration of both sodium alginate and coating polymer resulting in the
formation of larger microbeads entrapping greater amounts of the drug.
• AIM AND OBJECTIVE OF STUDY
The objectives of the study are :
• To know what are microbeads.
• To study how microbeads are prepared.
• To study the uses of microbeads
• PLAN OF WORK
• To search the review articles on the topic.
• Literature searches all the related items for specific topic.
• Collection of data or dissertation literature synopsis writing and preparing the
presentation.
• Abstracting the literature for compilation various chapters of dissertation such as
introduction review of literature etc.
• Final compilation of dissertation with conclusion and reference.
• METHODOLOGY
The following chemicals were procured from: aceclofenac (Rds Laboratory), Sodium alginate
(Marine chemicals), Potato starch (SSP Pvt Limited), Potassium dihyrogen phosphate (Vishnu
Priya Chemicals Pvt Ltd), Sodium hydroxide (Sakthy Sunder Acids Pvt Ltd) and calcium
chloride (Halocarbon Products Corporation)
Extraction of potato starch
Potatoes (1 kg) were washed carefully in tap water, dried and processed through a juice presser
(Moulinex). The residual is filtrated through a sieve (mesh 125 lm) with addition of 1 L tap
water removing cell wall material. To the residual starch slurry (final volume 2 L) is added 2
mL 38–40% sodium bisulphate solution and the slurry stands to settle for 1/2 hour. The pellet
of starch is washed two times in 1 L tap water and allowed to stand for 1/2 hour. Finally the
starch is dried at room temperature on filter paper over night.
Testing properties of potato starch from different scales of isolations—
A ringtest Bente Wischmann, Tina Ahmt, Ole Bandsholm et.al Journal of Food Engineering
79 (2007) 970–978
Procedure for preparation of Aceclofenac micro beads [10-12]
Accurately weighed drug was dissolved in acetone (solution 1). Sodium alginate and potato
starch was dissolved in water (solution 2). Then solutions 1 was mixed with solution 2 (Table
1). The mixture was placed in a beaker with constant stirring using magnetic stirring until
homogenous solution is obtained. It is then taken in a glass syringe and injected into calcium
chloride solution (5%) to form micro beads. Glutaraldehyde (3-4ml) is added to CaCl 2 solution
as a cross linking agent. Micro beads were filled and dried in a low temperature (40 0C).
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