CHU YUAN SHAN 260110152009

PLGA (EMULSIFIER)

Introduction

Poly(lactide-co-glycolide) (PLGA) is a synthetic copolymer of lactic acid

(a-hydroxy propanoic acid) and glycolic acid (hydroxy acetic acid). Lactic acid
contains an asymmetric carbon atom, and therefore has two optical isomers: L(+)
lactic acid and D(-) lactic acid. Lactic acid is present in nature as either an
intermediate or an end product in carbohydrate metabolism. It is widely distributed
in all living creatures (man, animals, plants, and microorganisms). Glycolic acid
occurs in nature to a limited extent. Poly(lactide-co-glycolide) degrades in vivo to
innocuous products. Its final degradation products are lactate (salt form of lactic
acid) and glycolate (salt form of glycolic acid).

Poly(lactide-co-glycolide) can be synthesized by direct polycondensation of

lactic acid and glycolic acid. However, the most efficient route to obtain high-
molecular weight (MW) copolymers is the ring opening polymerization of lactide
and glycolide. Lactide and glycolide are the cyclic diesters of lactic acid and
glycolic acid, respectively, and they are prepared by thermal degradation of lactic
and glycolic acid oligomers, respectively.

Figure 1. Structure of PLGA

Particles synthesised from biocompatible synthetic polymers are an

attractive alternative emulsifier. Compared with particles traditionally used, latex
particles have the advantage of being relatively monodisperse, giving greater
control over the drop size. Synthetic routes that produce polymeric particles with a
wide range of functional surface groups have been established. This flexibility
offers improved control of particle wetting. Altering the properties of particle-
stabilised emulsions typically involves changing the proportions of the liquid
phases, using different particles or adding surfactants. In contrast, changing the
wettability of latex particles with surfaces coated by ionizable carboxylic acid
groups, for example, simply involves changing the pH or ionic strength.

One of the most frequently studied and widely used polymers of

pharmaceutical interest is poly(lactic acid) (PLA) and its copolymers with glycolic
acid (PLGA). Due to the different crystallinity and hydrophobicity of lactic and
glycolic acid, ‘custom-made’ particles may be synthesised for the specific needs of
different applications. The properties of PLGA particles, including their surface
hydrophobicity, can be adjusted by varying the copolymer composition [29] and
the ratio of the components [30] or by chemically modifying the polymer surface
[31]. Another advantage is that non-toxic lactic and glycolic acids are produced
when these copolymers decompose due to enzymatic or hydrolytic reactions. Here,
we describe the first evaluation of nanoparticles of PLGA as particulate emulsifiers.
The surface properties of the particles were characterised by measuring the
charging behaviour of the particles and the oil–water wetting behaviour of PLGA
films. The mechanisms by which PLGA nanoparticles impart stability to emulsions
were investigated by determining the influence of the particle concentration on drop
stability and size.

Polymer name Poly(lactide-co-glycolide) (PLGA)

Synonyms Polyglactin;DL- PLGA
Chemical name 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, polymer with 1,4-
dioxane-2,5-dione
Structure

Molecular 2000 to >100 000

weight

Characteristics  Aliphatic polyesters are a group of synthesized

homopolymers or copolymers. They are nontoxic and
can easily be fabricated into a variety of novel devices,
such as rods, screws, nails, and cylinders. The
polymers are commercially available in varying
molecular weights as both homopolymers and
copolymers. Molecular weights of polyesters range
from 2000 Da to greater than 100 000 Da.
  Comonomer ratios of lactic acid and glycolic acid (or
lactide and glycolide) for poly(DL-lactide-co-
glycolide) range from 85 : 15 to 50 : 50.
 Polymer composition and crystallinity play important
roles in the solubility of these aliphatic polyesters. The
crystalline homo- polymers of glycolide or glycolic
acid are soluble only in strong solvents, such as
hexafluoroisopropanol.
 The crystalline homopolymers of lactide or lactic acid
also do not have good solubility in most organic
solvents. However, amorphous polymers of DL-
lactide or DL-lactic acid and copolymers of lactide or
lactic acid with a low glycolide or glycolic acid
content are soluble in many organic solvents
 Aliphatic polyesters are slightly soluble or insoluble
in water, methanol, ethylene glycol, heptane, and
hexane.

Benefit  can impart kinetic stability to emulsions by attaching

to the oil–water interface and forming a physical
barrier to drop coarsening
 Their biodegradation products are nontoxic,
noncarcinogenic, and nonteratogenic.
 No incompatibility

Preparation and characterisation of PLGA-stabilised emulsions

Emulsions were prepared by mixing oil and aqueous PLGA dispersions

together using a rotor–stator mixer (Ingenieurbüro CAT X1030D, M. Zipperer
GmbH) with a 10 mm diameter shaft operated at 1300 rpm. The type of emulsion
formed was tested by observing whether a drop of emulsion dispersed when added
to a small volume of pure water or oil. Emulsion sizes were measured by laser
diffraction (Malvern Mastersizer). Emulsions were diluted with MilliQ water to the
ratio of 1/100 and measured in the spec- ified cells at 20 ± 0.5 °C. The volume-
weighted average drop size (D(4, 3)) and the uniformity of the distributions (U)
were used in the analysis of emulsion size distributions. U is the extent of deviation
from the median in the distribution. The degree of creaming and phase separation
was recorded by visual inspection of samples stored in glass vials at ambient
temperatures. The emulsion structure was visualised using Cryo-Scanning Electron
Microscopy (cryo-SEM) to image fractured surfaces of frozen emulsions using a
Philips XL30 Field Emission Scanning Electron Microscope fitted with a CT1500
HR Low Temperature Cryo system.

Mechanism of PLGA as a emulsifier

It has been demonstrated that PLGA nanoparticles are effective Pickering

emulsifiers. In the special case of oils that dissolve PLGA, emulsions are instead
stabilised by polymer molecules. The PLGA particles were synthesised by
interfacial deposition using PVA as a stabilising surfactant. Measurements of the
particle charging behaviour indicated that there are both electrostatic and steric
contributions to dispersion stability. The presence of the relatively hydrophilic PVA
molecules on the particle surfaces means that they preferentially stabilise oil-in-
water emulsions formed from a wide range of oils (polar and non-polar). Uniform
drop size distributions are readily formed by mechanical mixing, providing that the
mixing time is controlled. Emulsion structure and stability is determined by the
amount of particles present.

It is well documented that dispersions of nanometre-sized PLGA particles

can be prepared by interfacial deposition. PLGA precipitates at the interface and
particles form rapidly. In most cases, a surfactant is required to stabilise the
polymeric particles as they condense in the aqueous phase. We chose to use the
neutral water-soluble polymer PVA to impart kinetic stability to the nanoparticle
dispersions. Incorporation of PVA molecules into the PLGA nanoparticle surfaces
reduces the particle hydrophobicity sufficiently for the particles to preferentially
stabilise oil-in-water emulsions.

PLGA nanoparticles can impart kinetic stability to emulsions by attaching

to the oil–water interface and forming a physical barrier to drop coarsening. The
(natural) surface hydrophobicity of the PLGA particles is also an important factor
in the colloidal interactions that affect drop stability. Particles can only attach to
drop surfaces providing that they approach closely enough for the thin liquid film
to rupture and for the three phase contact line formed to establish a stable wetting
perimeter. Electrostatic repulsive interactions between the particles and droplets in
water, however, generate an energy barrier to close approach. The PLGA particles
are weakly negatively charged. Droplets of non-polar oils, such as dodecane, are
weakly negatively charged due to adsorption of hydroxide ions. Hydrolysis will
generate an additional source of negative surface charges on droplets of polar oils,
such as isopropyl myristate. The hydrophobic attractions between PLGA particles
and the oil droplets dominate, however, and heterocoagulation occurs. Thus, in all
the cases studied here, the particles stabilise oil- in-water emulsions.
References

Rowe, C. Raymond. 2009. Handbook of Pharmaceutical Excipients 6th Edition.

USA: RPS Publishing.

Whitby, C. 2012. Poly(lactic-co-glycolic acid) as a particulate emulsifier. Journal

of Colloid and Interface Science. 375 (2012) 142–147.