International Journal of Pharmaceutics 466 (2014) 109121

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Polyoxylglycerides and glycerides: Effects of manufacturing

parameters on API stability, excipient functionality and processing
Vincent Jannin a, *, Jean-David Rodier a , Jasmine Musakhanian b
a
b

Gattefoss SAS, 36 chemin de Genas, Saint-Priest cedex 69804, France

Gattefoss Corporation, Plaza I, 115 West Century Road Suite 340, Paramus, NJ 07652, USA

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 10 January 2014
Received in revised form 13 February 2014
Accepted 2 March 2014
Available online 5 March 2014

Lipid-based formulations are a viable option to address modern drug delivery challenges such as
increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or
sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol
(glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients
used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more
commonly used in pharmaceutical drug products but there is still a lack of understanding of how the
manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within
the drug product.
In that regard, this review summarizes the key parameters to look at when formulating with lipid-based
excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality.
The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the
extraction and renement processes. Then, the key parameters during the manufacturing process
inuencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are
discussed in relation with their intended functionality and ability to interact with APIs and others
excipients within the formulation.
2014 Elsevier B.V. All rights reserved.

Keywords:
Lipid-based excipient
Polyethylene glycol ester
Critical quality attribute
Drug stability
Oxidation
Chemical reactivity

Contents
1.
2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nature of lipids/excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Glycerides denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Natural sources of lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Extraction and renement of lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
2.4.
Manufacture of lipid excipients glycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Interesterication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.1.
2.4.2.
Esterication, fat splitting, and transesterication . . . . . . . . . . . . . . . . . . .
Critical excipient characteristics: benets and interactions with other components
2.5.
Polyoxylglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nature of excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
3.2.
Manufacturing processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Alcoholysis of triglycerides with PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Direct esterication of fatty acids or methyl esters alcoholysis . . . . . . . . .
3.2.2.
3.2.3.
Ethoxylation of fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Critical excipient characteristics: benets and interactions with other components
3.3.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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in drug products
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in drug products
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* Corresponding author at: 36 chemin de Genas, Saint-Priest cedex 69804, France. Tel.: +33 472 229838; fax: +33 478 904567.
E-mail addresses: vjannin@gattefosse.com, vjannin69@gmail.com (V. Jannin).
http://dx.doi.org/10.1016/j.ijpharm.2014.03.007
0378-5173/ 2014 Elsevier B.V. All rights reserved.

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110

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

1. Introduction
Lipid excipients have a wide range of applications in
pharmaceuticals, food and consumer products. Liquid glycerides
are commonly used as solubilizers for lipophilic active pharmaceutical ingredients (API) whereas semi-solid and solid glycerides
serve as matrix formers in sustained release tablets and capsules
(Barthlmy et al., 1999; Jannin et al., 2006); as processing aids in
the formation of dispersions or multi particulate systems (Jannin
et al., 2003; N0 Diaye et al., 2003); and as coatings for taste masking,
prolonged release or lubrication (Jannin and Cuppok, 2013; Patil
et al., 2011). Polyoxylglycerides on the other hand are utilized as
solubility and bioavailability enhancers in self emulsifying systems
(Chambin et al., 2009; Fernandez et al., 2009; Porter et al., 2007;
Williams et al., 2013). These examples help demonstrate a
physical-chemical versatility which is inherently linked to the
nature of the lipid moieties which constitute these excipients.
Lipids (fats and oils) are generally dened by their polarity and
ability to interact with aqueous media, properties conditioned by
their composition. Fatty acids are the single common denominator
in all lipids. The functionality of lipids is linked to their structural
moieties, notably the type of fatty acids and their esters present.
Fatty acids are abundant in nature, found notably in dietary lipids
in the form of glycerides (fatty acid esters of glycerol). Glycerides
and their fatty acid components serve as building blocks for the
manufacture of lipid excipients. Depending on the intended
characteristics of the nal excipient, manufacturing may involve
a complex series of processes such as fractionation, esterication,
inter-esterication, alcoholysis, and multiple purication steps.
The functionality of the end product in the pharmaceutical dosage
form is therefore inherently linked to the source of the raw
materials and the manufacturing processes. Precise control of
composition and characteristics of lipid based excipient is essential
for their subsequent use as a pharmaceutical excipient. However,
these excipients can contain impurities that often contribute
signicantly to the degradation of API, as recently reviewed by Pr.
V. Stella (Stella, 2013).
The purpose of the review is to explain the impact of the
manufacturing processes of lipid-based excipients on the stability
of pharmaceutical dosage forms manufactured. Variations of
composition of these excipients deriving from natural products,
the potential presence of process aids, additives, and/or stabilizers
added during their extraction, rening, and processing can
profoundly impact the stability of the API in dosage forms made
using one or more of such excipients. In addition, different grades
of these lipid-based excipients have been introduced to provide

enhanced product differentiation or functionality while at the

same time being classied within the same general Pharmacopoeial monograph. Even if, lipid-based excipients are more and more
routinely used there is still a lack of understanding of how
excipient manufacturing processes either directly or indirectly
can impact the drug product stability.
Hence, this review aims to elucidate the key parameters
inuencing two groups of lipid excipients: glycerides, being fatty
acids esters of glycerol and polyoxylglycerides being fatty acid
esters polyethylene glycol (PEG) and glycerol presented in two
separate sections. The rst section starts by an introduction to the
chemistry of natural lipids (fats and oils), fatty acids and their
properties in relation to the extraction and renement processes
used. In addition, the critical characteristics of these excipients on
their functionality and ability to interact with other materials and
drug substances will be discussed.
2. Nature of lipids/excipients
2.1. Glycerides denition
Glycerides are the primary components of dietary lipids (fats and
oils). Lipids are fatty acids and their derivatives, and substances related
biosynthetically or functionally to these compounds (Christie, 1987).
Lipids are amphiphilic due to their dual molecular structure i.e. the
lipophilic portion consisting of fatty acid(s) and the hydrophilic
portion to which the fatty acid(s) are esteried (glycerol in the case of
glycerides) (Jannin et al., 2008). They can be divided in two groups
depending on their interaction with water (Larsson et al., 2006).
The rst group relates to non-polar lipids that are non-miscible
with water. Oils and fats are mainly composed of triacylglycerols
(also known as triglycerides) and are the main components of this
group. Triacylglycerols are composed of three fatty acids (acyl
groups) esteried to glycerol (see Fig. 1). Their partial glycerides
derivatives: diacylglycerols (diglycerides) are also non-polar.
Diacylglycerols are composed of two fatty acids esteried to
glycerol. Each diacylglycerol molecule exists as two different
isomers: 1,2- and 1,3-position. The migration of fatty acid from one
position to another is favored by temperature (even at room
temperature for liquids) and the equilibrium mixture is reached.
The second group consists of polar lipids that can interact with
water to form aqueous phases. Monoacylglycerols (monoglycerides) is one example of polar lipids. They can exist as two isomers
as 1- (which is equivalent to the 3-) and 2-position. The 1-isomer is
largely predominant in the equilibrium mixture reached after acyl
migration.

Fig. 1. Structures of acylglycerols: a. triacylglycerol; b. 1,2-diacylglycerol; c. 1-monoacylglycerol. The fatty acid used for this gure is stearic acid.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

111

Table 1
Nomenclature and characteristics of some fatty acids.
Common name

Fatty acid chain length and unsaturationa

Developed formula

Melting temperature ( C)

Caprylic acid
Capric acid
Lauric acid
Myristic acid
Palmitic acid
Stearic acid
Oleic acid
Ricinoleic acid
Linoleic acid
Linolenic acid
Eicosenoic
Behenic acid
Erucic acid

8:0
10:0
12:0
14:0
16:0
18:0
18: 1 (9c)
18: 1 (9c), OH (12)
18: 2 (9c12c)
18: 3 (9c12c15c)
20:1 (11c)
22:0
22:1 (13c)

CH3
(CH2)6COOH
CH3
(CH2)8COOH
CH3
(CH2)10COOH
CH3
(CH2)12COOH
CH3
(CH2)14
COOH
CH3
(CH2)16
COOH
CH3
(CH2)7CHQCH(CH2)7COOH
CH3
(CH2)5CHOHCH2CHQCH(CH2)7COOH
CH3
(CH2)4CHQCHCH2CHQCH
(CH2)7COOH
CH3
CH2CH=CH
CH2CHQCHCH2CHQCH(CH2)7COOH
CH3
(CH2)7CHQCH(CH2)9COOH
CH3
(CH2)20COOH
CH3
(CH2)7CHQCH(CH2)11COOH

16.5
31.6
44.8
54.4
62.9
70.1
16.0
5.5
5.0
11.0
23.0
80.0
33.8

a
Number of carbon atoms: number of unsaturated bonds (position and conformation of unsaturation). The letter c stands for the cis conformation of the unsaturation
bound by opposition to the trans conformation.

Since dietary lipids are the principal source of glycerides, the

building blocks for lipid excipients, a review of the current
practices that yield dietary lipids is necessary. The next section
therefore discusses the key processing steps and the potential
impact they may have on the composition and quality of the
rened lipids; considerations for selection of the natural source of
the lipids; and the principal differences in fatty acid structure and
composition.
2.2. Natural sources of lipids
Lipids may be obtained from animal or vegetable source. The
discussion herein is limited to vegetable oils given the abundance,
variety, safety, and overall preference by the pharmaceutical
industry.
Vegetable oils are obtained either from seeds, kernels, or
fruits. Each of these species has its unique composition and
repartition of fatty structures in terms of hydrocarbon chain
length and the number of unsaturated bonds in the chain. These
structural variations impact the physical properties of the
glycerides. The melting point of glycerides, for example, rises
with increasing hydrocarbon chain length but drops with
increasing number of double bonds otherwise referred to as
degree of unsaturation. Generally, the term oil is used to
describe glycerides that are liquid at or above room temperature

whereas fat is applied to solid or semi-solid glycerides. Fats

should not be confounded with solid waxes which are
chemically different from glycerides; they are esters of fatty
acids and long chain alcohol, mostly solids.
Fatty acids from vegetable origin are composed of an even
number of carbons ranging from 8 to 24. The more commonly
recurring fatty acids possess 12, 14, 16, or 18 carbon atoms (Naudet,
1992). Their nomenclature, composition, and melting temperatures are provided in Table 1.
Table 2 presents the fatty acid composition of some vegetable
oils used in the pharmaceutical industry either as excipients or as
raw materials for manufacturing lipid-based excipients (Merrien
et al., 1992; Padley et al., 1994).
It must be noted that apart from palm kernel and coconut oil
that contain mainly saturated medium chain fatty acids (C8, C10,
C12, C14, lauric acid being the major component), all other oils from
seeds, kernels or fruits are comprised predominantly of unsaturated long chain fatty acids (C16 and longer fatty acids). The two
most common fatty acids are oleic acid (olive, almond, apricot
kernel, palm) and linoleic acid (sunower, soybean, corn). New
varieties of oil seeds may be developed by natural breeding to
achieve a desirable fatty acid prole in term of safety, stability, and
or nutritional value. Examples of such varieties are low erucic acid
rapeseed oil (canola) and high-oleic acid sunower oil, both having
over 80% oleic acid content.

Table 2
Fatty acid composition of some vegetable oils used in the pharmaceutical industry (Merrien et al., 1992; Padley et al., 1994).
Vegetable oils

Caprylic
acid

Oils from seeds

Sunower oil
Soybean oil
Corn oil
Grape seed oil
Rapeseed oila
Sesame oil
Almond oil
Apricot kernel
oil
Cotton seed oil
Palm kernel oil
Castor oil
Oils from fruits
Olive oil
Palm oil
Coconut oil

and kernels

25

610

Capric
acid

35

510

High erucic acid rapeseed oil (HEAR).

Lauric
acid

Myristic
acid

<0.1

<0.2
<0.1
<0.3

<0.1

4451

<0.2
3954

0.51.3
1517

<0.1
12
1523

Palmitic
acid

Stearic
acid

Oleic
acid

Linoleic
acid

Linolenic
acid

Eicosenoic
acid

Erucic
acid

57
813
813
710
34
811
68
36

46
25
14
36
12
46
12
<2

1525
1726
2432
1422
916
3742
6482
5570

6270
5062
5562
6573
1116
3947
828
2035

<0.2
410
<2
<0.5
712
<0.6
<0.2
<1

<0.5
<0.4
<0.5
<0.2
713
<0.4
<0.1

4152

1731
710
1

13
23
1

1321
1218
3

3460
14
4

<1
<0.7

814
4346
611

36
46
14

6180
3741
411

314
912
12

<1
<0.4
<0.1

<0.5

Ricinoleic acid

90
<0.4

<0.2

112

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

can have signicant impact on the quality of the nished oil. These
include (Jannin et al., 2008):
 Free fatty acids present in the seed or produced during the





Fig. 2. Trituration steps to obtain oils from seeds and fruits.

2.3. Extraction and renement of lipids



Industrial operations involved in the processes from harvest

to extraction and renement of vegetable oils necessitate
multiple transfers to different processing locations. The
following section summarizes two main trituration schemes
(Fig. 2), applied to the extraction of oils from either seeds or
fruits (Laisney et al., 1992). The discussion that follows will
focus mainly on the steps that inuence the nal quality of the
nal product.
The trituration of seeds starts by a cleaning step using sieves
and magnets to remove dust, husks and iron impurities due to
harvesting. The seeds are then dried to reduce their water content
to 58%, which favors the safe storage of seeds and facilitates the
subsequent shelling, to separate the seed from the hull. The seeds
are then ground and attened with a rotating cylinder or grinder
and then heated to further reduce the water content of seeds;
increase their plasticity and uidity; coagulate the proteins
contained in the seeds; reduce the bioburden (by destroying
bacteria for example); deactivate thermo sensitive enzymes; and
eliminate thermo sensitive toxic substances. The bulk of the oil is
pressed out using either hydraulic presses (pressure ranging from 4
to 500 bars) or screw presses in a continuous process. A ltration or
centrifugation step can follow to clarify the oil. An additional
heating step at 8090  C under vacuum to dehydrate the oil down
to 0.1% of water may be applied and the residual oil remaining in
the seeds may be removed by chemical extraction. The latter
approach is faster, facilitates a higher yield and signicantly
reduces cost. After the extraction step, the organic solvent is
eliminated with residual content of no more than 300 ppm left
behind.
For fruits, trituration starts by washing with water to remove
leaves and other impurities. In the case of palm fruits a heating
step and picking off (substep removing fruits from the bunch) are
added to deactivate lipases that would otherwise go on
converting glycerides into glycerol and fatty acids. The fruits
are then ground without heating in order to crush the whole fruit
(with kernel and almond). The paste may be kneaded and heated
(elevated temperature for palm) before the oil begins to exude
(rst press). The pressing of the paste yields a liquid phase
consisting of oil and water that can be separated by decantation
or centrifugation to obtain virgin oil in the case of olive. In some
cases the pressing step can be replaced by a centrifugation of the
paste with water. Finally a ltration step either through a paper
lter or using ltration (adsorbing) earth could be implemented
to clarify the oil.
After trituration, oils are composed mainly of 9095%
triacylglycerols. They also contain some minor components that




extraction or storage of the oil through hydrolysis of acylglycerols.

Free fatty acids (unsaturated or not) are catalysts to the hydrolysis
of triacylglycerols leading to increased levels of partial glycerides.
Water the quantity of water in oil should be below 0.2% reduce
the hydrolysis of acylglycerols.
Partial glycerides diacylglycerols and monoacylglycerols are
formed during the hydrolysis of triacylglycerols. Monoacylglycerols are amphiphilic and can emulsify the oil with water during
the rening of oil impacting process efciency.
Phospholipids amphiphilic molecules like lecithin can limit the
efciency of the rening process. Phospholipid quantities may
vary from nearly zero in palm oil to 2% in soybean oil.
Colorants coloring agents such as b-carotene, chlorophyll and
other agents may be released due to the oxidation of the oil
during the extraction and rening processes.
Sugars present in the seed that serve to produce glycerol and
fatty acids.
Hydrocarbons either naturally present in oils (like squalene) or
formed during the extraction of oil from seeds with hexane.
Tocopherols also known as vitamin E, tocopherols are natural
antioxidants which provide natural chemical stability for oils. With
the exception of palm kernel and coconut oil that mainly consist of
saturated fatty acids, all vegetable oils contain tocopherols in
quantities ranging from 200 to 1200 ppm (Soulier and Farines,1992).
Other sterols, waxes, metals, aldehydes, ketones, and toxins,
can either be naturally occurring in some plants (gossypol in
cotton seed oil) or introduced by fungi to the crop (fungal
aatoxins), or by articial additives like pesticides or insecticides. These toxins are eliminated during renement.

Rening of crude oils helps remove many undesirable

components; renders oils as colorless, and as tasteless as possible;
and increases their stability against oxidation.
The rening of oils is a four-step process leading to the
concentration of triacylglycerols (>99%) (Denise, 1992):
 Deacidication: Also referred to as neutralization is carried out

to eliminate all free fatty acids. It is achieved either by chemical

(addition of sodium hydroxide) or physical means (vapor
striping). The chemical method has unique advantages as it
also eliminates sugars (mucilage that precipitate in presence of
alkali), metals, and toxic substances (gossypol, aatoxin, and
organophosphate insecticides).
 Washing of oils with water eliminates amphiphilic molecules
(phospholipids, monoacylglycerols, and soaps formed during the
deacidication step) after decantation.
 Bleaching of oils is conducted with adsorbing earths or activated
carbon.
 Deodorization of oils is carried out in presence of heat and under
vacuum to remove all volatile components including hexane. At
the end of this step the residual content of hexane should be
below 1 ppm. Water may be introduced to the bottom of the oil
vessel which readily boils off as steam, removing all water
soluble impurities. The process can also eliminate peroxides by
thermal degradation, some molecules responsible for taste and
smell such as aldehydes or ketones, some toxic organochloride
insecticides, and part of the tocopherols.
2.4. Manufacture of lipid excipients glycerides
Triacylglycerols can be used in their native form for nutritional
or pharmaceutical purposes. The development and manufacture of

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

113

and Table 3 summarizes information on the main catalysts and

conditions of use.

Fig. 3. Reaction scheme of the interesterication process with a reaction

temperature of 90  C and sodium methylate as catalyst.

unique and specialized lipid excipients however necessitates

modications and improvements to either fatty acid distribution
or degree of esterication to the glycerol molecule. A number of
processes are described below.
2.4.1. Interesterication
New glycerides may be prepared by redistribution of the fatty
acids on the glycerol backbone or by the combination of two
triglycerides by a process known as interesterication. Fig. 3 shows
the composition of a new glyceride obtained from the interesterication of two pure triacylglycerols (AAA and BBB).
Prior to the interesterication, product AAA consists only of
fatty acid A in all three ester positions. Triacylglycerol BBB, on the
other hand, consists of fatty acid B in all three positions. After
interesterication new acylglycerols are formed with combinations of fatty acids A and B in all positions.
Interesterication of oils or oil mixtures enables the redistribution of the fatty acids on the glycerol backbone. The process
improves the homogeneity of triglyceride molecules in terms of
fatty acid composition; it helps improve or control the physical
(melt) characteristics of oils/oil mixtures. It does not however alter
the degree of unsaturation or isomeric state of the starting product.
Interesterication reaction may be driven by chemicals or
enzymes. The reaction can be conducted at high temperatures
(250  C or more) or alternatively at lower temperatures in
presence of catalysts. Inert gas is invariably applied during
interesterication to prevent coloration of the mixture. The
catalysts used are alkali metals (NaOH, KOH) (Hurtova et al.,
1996), alkali metal alkoxides (CH3ONa) or metal catalysts (NaK).
Stannous derivatives have also been used (Sonntag, 1982a). The
mechanism of interesterication using CH3ONa is well described
in the literature (Liu, 2004). This reaction should be conducted
under inert gas to avoid coloration of the mixture. Many other
catalysts and conditions have been described (Sreenivasan, 1978),

2.4.2. Esterication, fat splitting, and transesterication

Partial glycerides (mono- and diacylglycerols) are commonly
used as pharmaceutical excipients. They are obtained mainly by
two processes: esterication or transesterication (Sonnet, 1999;
Sonntag, 1982a).
Esterication is a reaction where selected fatty acids are
recombined with glycerol. Free fatty acids are obtained through a
fat splitting step that entails the hydrolysis of oils to yield free fatty
acid and glycerol. These hydrolysates are then distilled to obtain
fatty acids of specic chain length which are subsequently
esteried anew with glycerol at a predened ratio to obtain the
intended partial glycerides. The process is commonly used to
synthesize medium chain triglycerides from coconut oil for
example.
Fat splitting can be achieved in many ways including:
saponication of oil i.e. reaction with a strong alkali, autoclaving
with a catalyst, high-pressure countercurrent splitting, or enzymatic degradation. The range of temperature used for splitting is
150260  C. Fat splitting is a homogeneous reaction involving
dispersion of water in the oil phase. The reaction is slow at the
onset because water has low dispersibility in triacylglycerols but
increases as di- and monoacylglycerols are formed until an
equilibrium between free fatty acid and glycerol is reached. To
push the reaction further, the free glycerol must be removed from
the reaction. Fat splitting is accelerated by mineral acids, metal
oxides, mainly zinc and magnesium oxides that form liposoluble
soaps that in turn drive the emulsication of oil with water and
speed up the process.
Esterication is the reverse reaction to fat splitting. Fatty acids
and glycerol react to form partial glycerides under high temperature and vacuum to remove water formed through the reaction.
That reaction can be conducted with or without catalyst, and
common catalysts include acid catalysts, sulfonic acids, zinc or tin
metals. Acid catalysts often darken the product and can lead to the
dehydration of unreacted glycerol to yield acrolein. In the absence
of a catalyst the reaction must be carried out at a temperature
above 250  C, which enables a reaction speed equivalent to that
obtained with a catalyst (Sonntag, 1982a).
Glycerolysis is a transesterication process in which triglycerides are reacted with glycerol to yield partial glycerides. The
process must be conducted in a reactor with efcient agitation
because glycerol and oil are not miscible during the early stage of
the reaction. Sodium hydroxide is often used as a catalyst and
forms soaps that promote the reaction by increasing the solubility
of glycerol in the oil phase. High processing temperature

Table 3
List of main catalysts used for interesterication and conditions of use.
Catalyst

Percentage of
use/reaction
temperature

Reaction
Time
(min)

Advantages

Disadvantages

Removal of the catalyst

Metal alkylate
e.g. sodium methylate
(CH3ONa)
Sodium-potassium alloy
(NaK)

0.12%
50120  C

50120

0.051%
25270  C

3120

Cost, ease of handling (dry

powder), low level of use (0.1%),
low temperature
Liquid, easy to handle, highly
reactive, short time reaction

Removal of the catalyst and soaps by acid

neutralization and water washing (Ahmadi
et al., 2008).
Deactivation with water.
Removal of soaps by washing

Sodium hydroxide (NaOH)

or potassium hydroxide
(KOH) + glycerol
Sodium hydroxide (NaOH)

0.050.1%
140160  C

90
Cost, easy to handle as an
(vacuum) aqueous solution

Loss of oil with the

formation of methyl esters
and soaps
Very reactive with water
and hydroxyl group,
hydrogen formation
Formation of partial
glycerides

0.52%
250  C

90
Cost, easy to handle as an
(vacuum) aqueous solution

Higher reaction
temperature, coloration of
the product

Neutralization of the catalyst with phosphoric

acid, removal of salts by washing with water
(Hurtova et al., 1996)
Removal the soaps by washing

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V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

(200250  C) is required in order to decrease the reaction time and

to increase the miscibility of oil with glycerol (Sonntag, 1982a,
1982b).
2.5. Critical excipient characteristics: benets and interactions with
other components in drug products
The most important or critical characteristics of glycerides
(Table 4) are structure of fatty acid(s), degree of saturation and
chain length, mono- and diglycerides content, and the presence of
natural antioxidants and or impurities. Among these characteristics we identied the critical quality attributes (CQA) of
excipients linked to the critical process parameters (CPP).
Fatty acid composition in naturally occurring lipids is dened
by the plant origin, i.e. species (see Table 2), variety or cultivar (for
example. high-oleic acid sunower low-erucic acid rapeseed
(Merrien, 1992; Morice, 1992)), geography/location, seasons,
temperature and rainfall (Richards et al., 2008). For synthetic
glycerides, fatty acid composition is controlled to different degrees
by the manufacturing process parameters as described in
Section 2.4. In addition to the nature of fatty acids, the ratio of
mono-, di- and triesters is the second most important parameter
dening the functionality of glycerides (Prajapati et al., 2012;
Witzeba et al., 2012).
The functionality of glycerides can be explained by the varying
roles they can play in drug delivery: as inert drug carriers for lling
into hard or soft shell capsules (e.g. medium and short chain
triglycerides); solubilizers for highly lipophilic drugs possessing
high Log P (long chain glycerides); by rate of digestion (fastest with
the shortest fatty acid chain length); by rate and degree of drug
micellization in vitro (Williams et al., 2012) and in-vivo due to
lipolysis (faster with partial glycerides or medium short chain fatty
acid esters); and mode of uptake into systemic circulation hepatic
vs. lymphatic the latter being slower, longer, and limited to long
chain glycerides.

In the case of solid-phase glycerides, the crystalline structure

of the molecules can add a new dimension to excipient
functionality, notably in relation to their ability to control drug
release (Hamdani et al., 2003). Aside from melt characteristics, all
solid-phase glycerides exhibit polymorphism. Hard fat triglycerides exhibit polymorphism with a monotropic evolution, leading
to denser and more stable polymorphs over time and temperature. Predicting such changes can help optimize the formulation
parameters to achieve a desired drug release prole. Monoglycerides on the other hand, have an enantiotropic polymorphism
whereby the most stable crystalline form changes reversibly as a
function of temperature, thus having little impact on drug release
in physiological conditions. Mixtures of glycerides exhibit a more
complex polymorphism depending on the relative quantity of
each esters and fatty acids (Gunstone and Padley, 1997; Small,
1986). Lipid polymorphism can be readily controlled by adapted
thermal treatments (Brubach et al., 2007) or by formulation
design.
Glycerides and more specically triacylglycerols are inert
entities with high compatibility with many commonly used
excipients. Glycerol esters containing saturated fatty acids are
mostly inert and naturally protected against oxidation. In the case
of unsaturated fatty acid esters, sensitivity to oxidation increases
with the degree of unsaturation (number of double bonds) where
oxidation can occur if left unprotected. Oxidation inherently
involves free radicals and auto-oxidation, and reactivity can be
limited by the natural presence of antioxidants in the crude or
virgin oil but accelerated in the presence of trace metals (Jannin
et al., 2008).
Auto-oxidation is the direct reaction of oxygen with the fatty
acid chain, and many parameters can induce this process which
occurs in three stages (Frankel, 2005a):
 Initiation the rst step of oxidation of the unsaturated fatty

chain is the formation of a free radical by the action of an

Table 4
Critical excipient characteristics for glycerides.
Excipient
characteristics

CQA Critical process parameters (CPP)

Processability

Chemical stability

In vivo functionality

Fatty acid chain length

Medium chain

No

Liquid

"

Fatty acid chain length

Saturated long chain
Fatty acid chain length
Unsaturated long
chain

No

No

Solid
"
(polymorphism)
Liquid
# Oxidative stability

" Solubility
enhancement
" Paracellular
permeability
" Controlled release
# Digestibility
" Solubility
enhancement of high
LogP drugs
" Lymphatic uptake
" Solubility by physical
drug inclusion (Chawla
and Saraf, 2011)

Glycerides composition Yes

Hydroxyl groups

Minor components
Natural antioxydants
Minor components
Free fatty acids

No

Impurities
Metal content
Impurities
Peroxides, aldehydes

No

Impurities
Soaps, alkaline
impurities

Yes

Yes

Yes

- Oil/glycerol ratio in the mixture

- Temperature and duration of synthesis
- Amount of catalysts

- Temperature and duration of synthesis

- Deodorization step

- Nitrogen blanketing during synthesis

Impact on

# Lipophilicity
" Dispersibility

" Chemical reactivity

" Oxidative stability

" Chemical reactivity

#
"
#
"

and packaging

- Type of catalysts
- Neutralization/Filtration step

" Dispersibility

Oxidative stability
Chemical reactivity
Oxidative stability
Chemical reactivity

" Chemical reactivity

" Solubility
enhancement
# Controlled release

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

initiator. The initiator may be the dissociation of hydroperoxide

by action of temperature, light or metals.
 Propagation radicals react with oxygen and produce new
hydroperoxides. Oxygen reacts selectively with allylic hydrogens
to form hydroperoxides.
 Termination recombination of two radicals to form non-radical
products.
Hydroperoxides can react with API or other excipients and
oxidize them. The allylic hydrogens play an important role during
this oxidation process. The more double bonds are contained in a
fatty acid chain, the more oxidation occurs in the product, as such
the oxidation rate of polyunsaturated fatty acids (PUFA), is greater
than monounsaturated ones. For example, auto-oxidation of
methyl linoleate is 40 times greater than methyl oleate, due to
the presence of a methylene (
CH2
) group entrapped between
two double bonds (Frankel, 2005b).
Hydroperoxides split up into degradation products following a
homolytic b-scission. This mechanism, inuenced by temperature
and metals as catalysts, leads to the formation of various organic
degradation products that can alter the quality of the excipient.
Families of these secondary degradation products include:
 Volatile compounds such as aldehydes (e.g. hexanal, 2-octenal,

propanal), ketones (e.g. 1-octene-3-one, 3-octene-2-one), alcohols (e.g. pentanol), and alkanes (e.g. pentane, heptane) (Frankel,
2005c).
 Non-volatile compounds such as oligomeric products obtained
by dimerization of hydroperoxides, oxidized esters, oxidized
fatty acids, and core aldehydes (high molecular weight
oxoglycerides).
Plant lipids are naturally protected against oxidation due to
presence of tocopherols (Frankel, 2005d) in quantities ranging
from 200 to 1200 mg/kg in non-rened state (Soulier and Farines,
1992). Their presence in oils and fats is always benecial to the
oxidative stability of API (Takahashi et al., 2003), but the rening
process can reduce drastically their content. Therefore, depending
on the natural variability of oil and the production parameters
described in Section 2.4, tocopherols content may vary by source,
inducing a difference in the oxidative stability of the nal products.
Antioxidants may be articially added to the rened oil, a practice
reserved mainly for oils destined for the food market. Pharmaceutical grade raw materials do not contain additives and protected
against oxidation merely by process and packaging controls. Iodine
value (degree of unsaturation), peroxide value (measure of
oxidative species present) and acid value (measure of free fatty
acids) are examples of controls relating to the quality of glycerides
and lipid excipients in general.

115

Some pharmaceutical preparations may be sensitive to free

hydroxyl groups (monoglycerides > diacylglycerols > triacylglycerols) thus hydroxyl value. In the manufacture of suppository bases
for example, hydroxyl value may be a key parameter inuencing
the rate of crystallization/solidication of pessaries. In the
presence of heat, there is also potential for some ingredients or
API to react with the free hydroxyl groups of the glycerides.
Formulations that are sensitive to such reactions therefore require
excipients with lowest possible hydroxyl value.
Whenever catalysts are used in the manufacturing of synthetic
glycerides, a neutralization step and subsequent removal of the
catalysts are carried out. The efciency of the neutralization and
removal of the residual alkaline impurities is assessed by an
alkaline impurities test with allowable limits well below 50 ppm
NaOH with as low as 0 ppm Na OH.
3. Polyoxylglycerides
3.1. Nature of excipients
Polyoxylglycerides (macrogolglycerides in the European Pharmacopeia) are complex excipients obtained by reacting glycerides
with polyoxyethylene glycols (PEG). The process yields mixtures of
mono-, di-, and triacylglycerols (Fig. 1) and mono- and diesters of
PEG (Fig. 4).
Whereas processing parameters have signicant impact on the
end product, the raw material (glycerides and PEG) properties are
arguably most crucial dening the molecular make up and thus
the physical-chemical behavior of polyoxylglycerides. Glycerides
are discussed in the previous section and before delving into the
manufacture and critical aspects of polyoxylglycerides, a short
discussion of PEG in this section is necessary.
Polyoxyethylene glycols (PEG) or polyethylene oxides (macrogols in the European Pharmacopoeia) are polymers of ethylene
oxide with the following structure: HO(CH2
CH2
O)n
H. PEG
are identied by a number which may stand either for the average
number of ethylene oxide units or for the mean molecular weight
of the polymer. For example a PEG with 32 ethylene oxide units
possesses a molecular weight of 1500 Da and could be identied
either as PEG-32 or PEG 1500. PEGs with molecular weight below
600 Da are viscous liquids and above 1000 Da are solids at room
temperature. All PEGs are freely soluble in water.
The denition of polyoxylglycerides in the compendia however
is not always as pointed and at times a single monograph may
encompass a range of polyoxylglycerides. Table 5 presents the
monographs listed in the current edition of USP-NF for polyoxylglycerides.
Each of the polyoxylglyceride monographs may cover a range of
excipients depending on the type of PEG and the ratio of glycerides
to PEG used in the manufacturing process. For example, the lauroyl

Fig. 4. Chemical structures of PEG esters comprised in polyoxylglycerides: a. PEG-8 monocaprylate. b. PEG-8 dicaprylate.

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V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

Table 5
Polyoxylglycerides listed in the USP-NF.
USP-NF monograph

Main fatty acid/vegetable oil source

Molecular weight of PEG

used

Physical appearance

Behenoyl polyoxylglycerides

C22:0/hydrogenated high erucic acid rapeseed oil (HEAR)

400

Caprylocaproyl
polyoxylglycerides
Lauroyl polyoxylglycerides

C8:0 and C10:0/medium chain triglycerides from coconut oil or hydrogenated palm 200400
kernel oil
C12:0/coconut oil or hydrogenated palm/palm kernel oil
3001500

Stearoyl polyoxylglycerides

C18:0/hydrogenated palm oil

3004000

Oleoyl polyoxylglycerides
Linoleoyl polyoxylglycerides

C18:1/apricot kernel oil

C18:2/corn oil

300400
300400

Pale-yellow waxy
solid
Pale-yellow oily
liquid
Pale-yellow waxy
solid
Pale-yellow waxy
solid
Amber oily liquid
Amber oily liquid

polyoxylglycerides monograph indicates PEGs with molecular

weights ranging from 300 to 1500 Da. Two currently marketed
excipients fall in this category involving PEG 300 (PEG-6) or PEG
1500 (PEG-32). These excipients possess different surfactant
properties due to the length of their PEG moieties. Lauroyl
polyoxyl-6 glycerides have a hydrophilic-lipophilic balance (HLB)
value of 9 whereas lauroyl polyoxyl-32 glycerides possess an HLB
of 11. Another major difference between two polyoxylglycerides,
apart from the size of the PEG moiety, can be in the amount of free
PEGs present, which is dependent on the ratios of the raw
materials used during the reaction, wherein an excess of PEG favors
the production of PEG esters.
Polyoxylglycerides can be manufactured by three different
processes:
 Alcoholysis of triglycerides with PEG.
 Direct esterication of fatty acids or methyl esters alcoholysis

(and subsequent mixing with partial glycerides).

 Ethoxylation of fatty acids (and subsequent mixing with partial

glycerides).

3.2. Manufacturing processes

Polyoxylglycerides can be obtained either by an alcoholysis/
transesterication of lipids by polyoxyethylene (PEG) or by mixing
PEG esters with glycerides. The nature of glycerides and their
production is presented in Section 2. This section describes the
alcoholysis/transesterication reaction pathway followed by the
manufacturing process of PEG esters.
Industrial transesterication or esterication reactions are
carried out in carbon-steel or stainless-steel reactors. Esterication
reaction is generally preferred as a batch process rather than as a
continuous one because of the long reaction times and the quantity
of water to be removed during the reaction (Hasenhuettl, 2000).
3.2.1. Alcoholysis of triglycerides with PEG
The raw materials, oils (triglycerides) and PEG, are introduced
in the reactor before the addition of a catalyst (generally an alkaline
homogeneous catalyst is used). The reaction is conducted at high
temperature under inert gases like nitrogen or under vacuum to
limit the introduction of oxygen and to avoid oxidative reactions.
After completion of the reaction, the catalyst is neutralized, and the
medium cooled down. The neutralized catalyst generally forms a
salt that is removed by a separation step such as ltration. The
reaction scheme is presented in Fig. 5.
The reaction pathway yields a complex mixture of triglycerides,
partial glycerides (mono- and diacylglycerols), PEG fatty acids
mono- and diesters, free glycerol and unreacted PEG and
triacylglycerols (Hamid et al., 2004).

The alcoholysis reaction described in Fig. 5 shows the

rearrangement of the positioning of the fatty acids on the glycerol
molecule. Homogeneous catalysts (soluble in the reaction mixture)
such as hydroxide, methoxide or alkali metal can be used. This
process requires a neutralization step and then the removal of salts
by ltration. The use of heterogeneous catalyst (insoluble in the
reaction mixture) to produce PEG fatty esters by transesterication
of methyl esters has also been reported (Climent et al., 2006).
These insoluble catalysts are then removed by ltration.
3.2.2. Direct esterication of fatty acids or methyl esters alcoholysis
PEG has two equivalent reactive OH groups able to be
substituted by a carboxylic acid function. The esterication
therefore results in a mixture of monoesters and diesters. The
scheme of the esterication reaction is presented in Fig. 6.
Reactors used for the esterication of fatty acid with PEG are
similar to those described for glycerides in Section 2.4. Fatty acids
and PEG are mixed together in a reactor. A catalyst can be added to
the medium to accelerate the reaction. The reactor contents are
heated to a temperature sufcient to activate the reaction. Water
can be partially eliminated by heat and by the application of inert
gas (nitrogen) or vacuum.
The reaction products are a mixture of mono- and diesters of
PEG. The ratio of the monoesters/diesters in the nished product
depends on the initial ratio of the raw materials, PEG/fatty acids.
Using a large excess of PEG over fatty acids leads to a high amount
of monoesters. PEG/fatty acid ratios of 6 to 12 are described for
manufacturing products with high monoesters content (Weil et al.,
1979). These conditions however produce also a high amount of
unreacted PEG. Thus, a higher ratio of monoesters/diesters is
associated with lower production yield after removal of the free
PEG.
Homogenous catalysts are often used to improve the process by
decreasing the reaction temperature and time. Acids are often used
as catalysts: p-toluenesulfonic acid, sulfuric acid, phosphoric acid
(Weil et al., 1979). Novel catalysts have been studied to increase the
selectivity of monoesters without using a large excess of PEG,
which is then difcult to eliminate. Zeolites have been compared
with classical homogenous catalyst p-toluenesulfonic acid (PTSA)
in esterication reaction between oleic acid and PEG 600 (Hamid
et al., 2004). The study shows a superior selectivity of the zeolites
to form PEG monoester compared to PTSA. Another recently
described process condition involves the use of high ratio of PEG/
fatty acid (10:1) combined with a supported enzyme (Novozym
435) as catalyst (Viklund and Hult, 2004). The unreacted PEG is
removed by repeated extraction using NaCl solution and ethyl
acetate. The reaction leads to a monoesters content between 77%
and 87%.
The second alcoholysis pathway for esterication of fatty acid
methyl esters with PEG is shown in Fig. 7.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

117

Fig. 5. Alcoholysis/transesterication reaction pathway to manufacture polyoxylglycerides.

The reaction is conducted at lower temperature than the

esterication process because the temperature needed to remove
methanol is lower than that required to evaporate water.
Metallic catalyst like sodium shows a high efcacy (Sonntag,
1982b) but homogenous catalysts like hydoxides or methoxides of
alkali metals are the most commonly used.
3.2.3. Ethoxylation of fatty acids
The third manufacturing process to obtain PEG esters is the
ethoxylation of fatty acids (Kosswig, 1998).
The rst step is the formation of an initiator for the ensuing
polymerization. It is obtained by reaction of an alkaline catalyst
(alkali metal, carbonate, hydroxide, alkoxide) with fatty acids
to form carboxylates. The carboxylates are then reacted
with ethylene oxide. Initially, all of the fatty acids are consumed
to form ethylene glycol monoesters (Fig. 8a), followed by
propagation of ethoxylation (Fig. 8b). As the reaction continues
under alkaline conditions, monoesters become engaged in a

transesterication reaction which leads to the formation of

diesters and free PEG (Fig. 8c).
3.3. Critical excipient characteristics: benets and interactions with
other components in drug products
Polyoxylglycerides are complex excipients, demonstrating
complex properties all dependent on the nature of the raw
materials and the processes used in their manufacture as
summarized in Table 6. Among these characteristics we identied
the critical quality attributes (CQA) of excipients linked to the
critical process parameters (CPP).
An important contributor to variability in polyoxylglycerides is
the inconsistencies in the raw material PEG. In effect, each grade
of PEG has a specic molecular mass distribution with a range
dependent on the manufacturer. The distribution can also be
different from batch to batch. PEG may be obtained in a number of
ways: interaction of ethylene oxide with water, ethylene glycol, or

Fig. 6. Direct esterication of PEG with free fatty acids.

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V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

Fig. 7. Alcoholysis of fatty acid methyl esters with PEG.

ethylene glycol oligomers. Generally, PEGs obtained by the

reaction between ethylene oxide and ethylene glycol are
preferred because the reaction leads to a polymer with an
uniform weight distribution (Kosswig, 1998) therefore a much
lower polydispersity. PEG are also an important source of
impurities such as ethylene oxide and 1,4-dioxane or alkali
catalysts such as sodium hydroxide, potassium hydroxide, or
sodium carbonate which are used to prepare low-molecularweight polyethylene glycol.
An important and yet less known aspect of PEG is their high
sensitivity to oxidation. The presence of free (unreacted) PEG in
polyoxylglycerides is an important contributor of oxidative
sensitivity.
A third parameter of variability in polyoxylglycerides relates to
the composition of oils. Vegetable oils containing a complex
composition of fatty acids will lead to numerous possible
combinations between these fatty acids and the different PEG
chains. Industrially, it is rare to use triacylglycerols composed of
only a single fatty acid type. Often oils are composed of various
fatty acids and their individual content specications fall within a

range. Likewise, in the case of the direct esterication pathway,

the fraction of distilled fatty acids will therefore follow a range.
Some fatty acids and their corresponding methyl esters with a
high purity (i.e. 9099% of a single component) are produced
industrially. This purication step result in a single component
free of unsaturated or unsaponiable matters (Formo, 1982).
Following hydrolysis of the oil, the fatty acids are puried by
distillation. The use of these high purity products can help
minimize variability in the nal polyoxylglycerides products.
Direct interactions between polyoxylglycerides and other
excipients or API, may be formulation dependent. Indirect
reactions however may stem from the presence of impurities
combined with the sensitivity of polyoxylglycerides to oxidation.
The susceptibility of polyoxylglycerides to oxidation relates
generally to the PEG moiety, to the presence of unsaturated fatty
acids, and to the presence of the impurities in the excipient and
from other ingredients in the drug formulation. Polyoxylglyceride
impurities may come from the raw materials themselves, may be
generated during their storage, the production of the excipient, or
post production

Fig. 8. Reaction scheme of the ethoxylation of fatty acids.

a Reaction of the alkaline form of fatty acids with ethylene oxide.
b Propagation of ethoxylation.
c Transesterication of PEG monoesters, formation of PEG diesters and free PEG under alkaline conditions.
This ethoxylation process, as well as the esterication of fatty acids with PEG, results in a mixture of PEG monoesters, PEG diesters, and free PEG.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

119

Table 6
Critical excipient characteristics for polyoxylglycerides.
Excipient
characteristics

CQA

Critical process parameters

Processability

Chemical stability

In vivo functionality

PEG composition
Low molecular mass
(<600 Da)
PEG composition
High molecular mass
(>1000 Da)
PEG esters composition
Free PEG

No

Liquid
" Dispersibility

" Chemical reactivity

" Hygroscopy

" Solubility enhancement

No

Solid (polymorphism)
" Hydration time

" Controlled release

Impact on

Yes

- Lipid/PEG ratio in the mixture

- Temperature and duration of synthesis
- Amount of catalysts

" Dispersibility

" Hygroscopy

" Paracellular uptake (PEG-8)

PEG esters composition

Free fatty acids

Yes

- Temperature and duration of synthesis

- Deodorization step

" Chemical reactivity

PEG esters composition

Monoesters

Yes

- Lipid/PEG ratio in the mixture

- Temperature and duration of synthesis
- Amount of catalysts

" Dispersibility
" HLB

" Solubility enhancement

PEG impurities
Dioxane

Yes

- Type of catalyst (acid catalyst)

- Temperature of process
- Deodorization step

" Toxicity

PEG impurities
Aldehydes, peroxides

Yes

- Nitrogen blanketing during synthesis

# Oxidative stability
" Chemical reactivity

PEG impurities
Alkaline impurities
Fatty acid composition

Yes

" Dispersibility

" Chemical reactivity

" Solubility enhancement

# Controlled release

and packaging

- Neutralization/Filtration step

See Table 4

Oxidative risks may be prevented by measures like the addition

of anti-oxidants, working under vacuum and/or nitrogen blanketing to protect the excipient and the formulation. Other controls
include minimizing exposure to heat, aeration, humidity, and light.
Simple routine testing for acid value, peroxides, and water content
can help assess oxidative changes following critical processing and
formulation steps.
Following the same scheme as fatty acid auto-oxidation, PEG
oxidation includes three steps (Kumar and Kalonia, 2006; Lloyd,
1961): initiation, propagation, termination.
Studies on polyoxyl derivatives show that a-hydroperoxides
degrade by the carbon-carbon bond scission of ethylene oxide unit
(EO) and leads to formaldehyde and formic acid formation
(Hamburger et al., 1975; Lloyd, 1956). The evolution of the physical
properties (cloudy point) veried during these studies suggests
that the scission occurs on the EO terminal unit and not in the core
of the PEG chain.
The degradation of a model compound such as tetraethylene glycol
(Glastrup, 1996) shows that in presence of high temperature (70  C)
and air (oxygen), the terminal EO unit (
O
CH2
CH2
OH)
degrades into formic acid in a few days (Glastrup, 1996). Similar
experiments conducted at 150  C in ambient atmosphere tend to the
same conclusions, as demonstrated by 13C NMR analysis (Mkhatresh
and Heatley, 2002). Other studies show that in PEG 400 aqueous
solutions, formaldehyde and formic acid are the major impurities,
beside acetaldehyde and acetic acid. The mechanisms by which these
impurities are formed in accelerated conditions (40 or 50  C in acidic
media) are described in (Hemenway et al., 2012).
Effects of pro-oxidant such as light and copper sulfate at 40  C
on the peroxidation of polyoxyl derivatives have been studied
(Hamburger et al., 1975). The induction phase is reduced by the
presence of these pro-oxidants. During the propagation step,
peroxide index increases dramatically then drops during the
termination step, traducing the conversion of peroxides into
degradation and terminal products.
Metals like Cu2+ and Fe3+ are strong peroxidation agents (Jaeger
et al., 1994). PEG-based products stored in dark conditions or

protected by antioxidant like butylated hydroxytoluene (BHT)

maintain a low peroxide index. However the peroxide value of
products stored in air-tight container will increase over time
(months) unless gases ush is provided after the opening. Other
phenolic compounds used as antioxidants for PEG have been
described (Lloyd, 1961).
The inuence of alkali metals (KOH, NaOH) have been studied
on the deformylation of the POE chain in presence of Cu2+
(Sakharov et al., 2001). Bases induce deprotonation of PEG and
the anion forms a complex with Cu2+, formic acid is then
produced. Copper forms a complex with the polyether chain and
not with the terminal hydroxyl groups of the PEG. Thus, the
stability of this complex is increased by the length of the PEG
chain.
Photo-oxidation studies (light irradiation at 300 nm, 60  C) on
PEG moieties also show the hydroperoxide formation on the
a-position of the ether bond (Gauvin et al., 1987). Degradation
products are formiates (formic acid esters). Peroxide can interact
with amino-acids (e.g. cystine) and proteins (Ha et al., 2002). Some
oxidative impurities can oxidize thiols function or Fe2+ into Fe3+
(Ashani and Catravas, 1980).
Oxidative substances can be eliminated by the action of a
reducer like sodium hydrogenosulte (NaHSO3). Sodium metabisulte (Na2S2O5) in aqueous solutions acts as an oxygen
scavenger and avoid the formation of hydroperoxides, precursors
of formaldehyde, formic acid or macro-aldehydes like PEGaldehydes (Hemenway et al., 2012). The puried product no
longer exhibits oxidative activity but the carbonyl compounds are
not eliminated (Ashani and Catravas, 1980). Another treatment to
prevent hydroperoxide formation is the removal of dissolved
oxygen in the PEG by applying a vacuum (Kumar and Kalonia,
2006).
Peroxides and aldehydes can be eliminated by sodium
thiosulfate of sodium borohydride (NaBH4) treatment (Ray and
Puvathingal, 1985).
Formaldehyde can interact with API, excipient and gelatin shells
containing NH
 group (Nassar et al., 2004).

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V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121

As glycerides, high molecular weight PEG and PEG esters can

crystallize in various polymorphs, mainly in zigzag or helical
conformation (Neyertz et al., 1994). The most stable polymorph
can be obtain either by controlling the crystallization rate of the
polyoxylglycerides or by treating the sample by a thermal
treatment after crystallization (Brubach et al., 2004; Jannin, 2009).
4. Conclusions
This review shows that the key excipient characteristics
impacting drug product quality and functionality derive from
the quality of raw materials used and the manufacturing process
parameters applied. Among these key characteristics, the lipidbased excipients CQAs are linked to the ester composition (mono-/
di-/triacylglycerols or mono-/diesters of PEG) traduced by the
hydroxyl value, and also to the presence of impurities or minor
components (free fatty acids, peroxides, aldehydes, soaps, alkaline
impurities and dioxane). The CPPs controlling the excipient quality
are the lipid/alcohol ratio in the reaction mixture, the quality of the
nitrogen blanketing, parameters used for synthesis leading to the
intended equilibrium of the composition (duration, temperature,
catalyst), and nally the rening steps eventually implemented
(deodorization, neutralization and ltration).
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