2. 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 pharma-ceutical
ingredients (API) whereas semi-solid and solid glycerides
serve as matrix formers in sustained release tablets and capsules
(Barthélémy et al., 1999; Jannin et al., 2006); as processing aids in
the formation of dispersions or multi particulate systems (Jannin
et al., 2003; N0Diaye 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 defined 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
final excipient, manufacturing may involve
a complex series of processes such as fractionation, esterification,
inter-esterification, alcoholysis, and multiple purification 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
significantly 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, refining, 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 classified within the same general Pharmacopoe-ial
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
influencing 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
first 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 refinement 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 – definition
Glycerides are the primary components of dietary lipids (fats and
oils). Lipids are fattyacidsand theirderivatives, 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 esterified (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
first 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) esterified to glycerol (see Fig. 1). Their partial glycerides
derivatives: diacylglycerols (diglycerides) are also non-polar.
Diacylglycerols are composed of two fatty acids esterified 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 (monoglycer-
ides) 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
figure is stearic acid.
110 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121
3. 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
refined 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 temper-
atures 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 unsatu-rated
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 (sunflower, soybean, corn). New
varieties of oil seeds may be developed by natural breeding to
achieve a desirable fatty acid profile in term of safety, stability, and
or nutritional value. Examples of such varieties are low erucic acid
rapeseed oil (canola) and high-oleic acid sunflower oil, both having
over 80% oleic acid content.
Table 1
Nomenclature and characteristics of some fatty acids.
Common name Fatty acid chain length and unsaturationa Developed formula Melting temperature (C)
Caprylic acid 8:0 CH3(CH2)6COOH 16.5
Capric acid 10:0 CH3(CH2)8COOH 31.6
Lauric acid 12:0 CH3(CH2)10COOH 44.8
Myristic acid 14:0 CH3(CH2)12COOH 54.4
Palmitic acid 16:0 CH3(CH2)14COOH 62.9
Stearic acid 18:0 CH3(CH2)16COOH 70.1
Oleic acid 18: 1 (9c) CH3(CH2)7CHQCH(CH2)7COOH 16.0
Ricinoleic acid 18: 1 (9c), OH (12) CH3(CH2)5CHOHCH2CHQCH(CH2)7COOH 5.5
Linoleic acid 18: 2 (9c12c) CH3(CH2)4CHQCHCH2CHQCH(CH2)7COOH
5.0
Linolenic acid 18: 3 (9c12c15c) CH3CH2CH=CHCH2CHQCHCH2CHQCH(CH2)7COOH
11.0
Eicosenoic 20:1 (11c) CH3(CH2)7CHQCH(CH2)9COOH 23.0
Behenic acid 22:0 CH3(CH2)20COOH 80.0
Erucic acid 22:1 (13c) CH3(CH2)7CHQCH(CH2)11COOH 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.
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
Capric
acid
Lauric
acid
Myristic
acid
Palmitic
acid
Stearic
acid
Oleic
acid
Linoleic
acid
Linolenic
acid
Eicosenoic
acid
Erucic
acid
Ricinoleic acid
Oils from seeds and kernels
Sunflower oil – – – – 5–7 4–6 15–25 62–70 0.2 0.5 –
Soybean oil – – – 0.2 8–13 2–5 17–26 50–62 4–10 0.4 –
Corn oil – – – 0.1 8–13 1–4 24–32 55–62 2 0.5 –
Grape seed oil – – – 0.3 7–10 3–6 14–22 65–73 0.5 0.2 –
Rapeseed oila – – – – 3–4 1–2 9–16 11–16 7–12 7–13 41–52
Sesame oil – – 0.1 0.1 8–11 4–6 37–42 39–47 0.6 0.4 –
Almond oil – – – – 6–8 1–2 64–82 8–28 0.2 0.1 –
Apricot kernel
oil
– – – – 3–6 2 55–70 20–35 1 – –
Cotton seed oil – – – 0.5–1.3 17–31 1–3 13–21 34–60 1 – –
Palm kernel oil 2–5 3–5 44–51 15–17 7–10 2–3 12–18 1–4 0.7 0.5 –
Castor oil 1 1 3 4 90
Oils from fruits
Olive oil – – – 0.1 8–14 3–6 61–80 3–14 1 0.4 –
Palm oil – – 0.2 1–2 43–46 4–6 37–41 9–12 0.4 – –
Coconut oil 6–10 5–10 39–54 15–23 6–11 1–4 4–11 1–2 0.1 0.2 –
a High erucic acid rapeseed oil (HEAR).
V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121 111
4. 2.3. Extraction and refinement of lipids
Industrial operations involved in the processes from harvest
to extraction and refinement 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 influence the
final quality of the
final 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 5–8%, 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
flattened with a rotating cylinder or grinder
and then heated to further reduce the water content of seeds;
increase their plasticity and
fluidity; 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
filtration or
centrifugation step can follow to clarify the oil. An additional
heating step at 80–90 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 significantly
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
(first 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
filtration step either through a paper
filter or using
filtration (adsorbing) earth could be implemented
to clarify the oil.
After trituration, oils are composed mainly of 90–95%
triacylglycerols. They also contain some minor components that
can have significant impact on the quality of the
finished oil. These
include (Jannin et al., 2008):
Free fatty acids – present in the seed or produced during the
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. Monoacylgly-
cerols are amphiphilic and can emulsify the oil with water during
the refining of oil impacting process efficiency.
Phospholipids – amphiphilic molecules like lecithin can limit the
efficiency of the refining 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 refining 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
quantitiesrangingfrom200to1200 ppm(SoulierandFarines,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
aflatoxins), or by artificial additives like pesticides or insecti-cides.
These toxins are eliminated during refinement.
Refining of crude oils helps remove many undesirable
components; renders oils as colorless, and as tasteless as possible;
and increases their stability against oxidation.
The refining of oils is a four-step process leading to the
concentration of triacylglycerols (99%) (Denise, 1992):
Deacidification: 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, aflatoxin, and
organophosphate insecticides).
Washing of oils with water eliminates amphiphilic molecules
(phospholipids, monoacylglycerols, and soaps formed during the
deacidification 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
Fig. 2. Trituration steps to obtain oils from seeds and fruits.
112 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121
5. unique and specialized lipid excipients however necessitates
modifications and improvements to either fatty acid distribution
or degree of esterification to the glycerol molecule. A number of
processes are described below.
2.4.1. Interesterification
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 interesterification. Fig. 3 shows
the composition of a new glyceride obtained from the interester-
ification of two pure triacylglycerols (AAA and BBB).
Prior to the interesterification, 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
interesterification new acylglycerols are formed with combina-tions
of fatty acids A and B in all positions.
Interesterification of oils or oil mixtures enables the redistri-
bution 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.
Interesterification 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
interesterification 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 interesterification 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),
and Table 3 summarizes information on the main catalysts and
conditions of use.
2.4.2. Esterification, fat splitting, and transesterification
Partial glycerides (mono- and diacylglycerols) are commonly
used as pharmaceutical excipients. They are obtained mainly by
two processes: esterification or transesterification (Sonnet, 1999;
Sonntag, 1982a).
Esterification 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 specific chain length which are subsequently
esterified anew with glycerol at a predefined 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:
saponification of oil i.e. reaction with a strong alkali, autoclaving
with a catalyst, high-pressure countercurrent splitting, or enzy-matic
degradation. The range of temperature used for splitting is
150–260 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 emulsification of oil with water and
speed up the process.
Esterification is the reverse reaction to fat splitting. Fatty acids
and glycerol react to form partial glycerides under high tempera-
ture 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 transesterification process in which triglycer-
ides are reacted with glycerol to yield partial glycerides. The
process must be conducted in a reactor with efficient 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
Fig. 3. Reaction scheme of the interesterification process with a reaction
temperature of 90 C and sodium methylate as catalyst.
Table 3
List of main catalysts used for interesterification 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)
0.1–2%
50–120 C
50–120 Cost, ease of handling (dry
powder), low level of use (0.1%),
low temperature
Loss of oil with the
formation of methyl esters
and soaps
Removal of the catalyst and soaps by acid
neutralization and water washing (Ahmadi
et al., 2008).
Sodium-potassium alloy
(NaK)
0.05–1%
25–270 C
3–120 Liquid, easy to handle, highly
reactive, short time reaction
Very reactive with water
and hydroxyl group,
hydrogen formation
Deactivation with water.
Removal of soaps by washing
Sodium hydroxide (NaOH)
or potassium hydroxide
(KOH) + glycerol
0.05–0.1%
140–160 C
90
(vacuum)
Cost, easy to handle as an
aqueous solution
Formation of partial
glycerides
Neutralization of the catalyst with phosphoric
acid, removal of salts by washing with water
(Hurtova et al., 1996)
Sodium hydroxide (NaOH) 0.5–2%
250 C
90
(vacuum)
Cost, easy to handle as an
aqueous solution
Higher reaction
temperature, coloration of
the product
Removal the soaps by washing
V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121 113
6. (200–250 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: benefits 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 character-
istics we identified the critical quality attributes (CQA) of
excipients linked to the critical process parameters (CPP).
Fatty acid composition in naturally occurring lipids is defined
by the plant origin, i.e. species (see Table 2), variety or cultivar (for
example. high-oleic acid sunflower 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
defining 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
filling
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 triglycer-
ides exhibit polymorphism with a monotropic evolution, leading
to denser and more stable polymorphs over time and tempera-
ture. Predicting such changes can help optimize the formulation
parameters to achieve a desired drug release profile. Monogly-
cerides 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 specifically 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
first 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) Impact on
Processability Chemical stability In vivo functionality
Fatty acid chain length
Medium chain
No – Liquid
Solubility
enhancement
Paracellular
permeability
Fatty acid chain length
Saturated long chain
No – Solid
(polymorphism)
Controlled release
#
Digestibility
Fatty acid chain length
Unsaturated long
chain
No – Liquid
#
Oxidative stability
Solubility
enhancement of high
LogP drugs
Lymphatic uptake
Glycerides composition
Hydroxyl groups
Yes - Oil/glycerol ratio in the mixture
- Temperature and duration of synthesis
- Amount of catalysts
#
Lipophilicity
Dispersibility
Chemical reactivity
Solubility by physical
drug inclusion (Chawla
and Saraf, 2011)
Minor components
Natural antioxydants
No – –
Oxidative stability –
Minor components
Free fatty acids
Yes - Temperature and duration of synthesis
- Deodorization step
–
Chemical reactivity –
Impurities
Metal content
No – –
#
Oxidative stability
Chemical reactivity
–
Impurities
Peroxides, aldehydes
Yes - Nitrogen blanketing during synthesis
and packaging
–
#
Oxidative stability
Chemical reactivity
–
Impurities
Soaps, alkaline
impurities
Yes - Type of catalysts
- Neutralization/Filtration step
Dispersibility
Chemical reactivity
Solubility
enhancement
#
Controlled release
114 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121
7. 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, influenced 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), alco-hols
(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-refined state (Soulier and Farines,
1992). Their presence in oils and fats is always beneficial to the
oxidative stability of API (Takahashi et al., 2003), but the refining
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
final products.
Antioxidants may be artificially added to the refined oil, a practice
reserved mainly for oils destined for the food market. Pharmaceu-tical
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.
Some pharmaceutical preparations may be sensitive to free
hydroxyl groups (monoglycerides diacylglycerols triacylglycer-
ols) – thus hydroxyl value. In the manufacture of suppository bases
for example, hydroxyl value may be a key parameter influencing
the rate of crystallization/solidification 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 efficiency 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 Phar-
macopeia) 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 significant impact on the
end product, the raw material (glycerides and PEG) properties are
arguably most crucial – defining 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 (macro-gols
in the European Pharmacopoeia) are polymers of ethylene
oxide with the following structure: HO(CH2CH2O)nH. PEG
are identified 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 identified
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 definition 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 polyox-
ylglycerides.
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.
V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121 115
8. 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
PEG’s 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 esterification 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/
transesterification 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/transesterification reaction pathway followed by the
manufacturing process of PEG esters.
Industrial transesterification or esterification reactions are
carried out in carbon-steel or stainless-steel reactors. Esterification
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
filtration. 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
filtration. The use of heterogeneous catalyst (insoluble in the
reaction mixture) to produce PEG fatty esters by transesterification
of methyl esters has also been reported (Climent et al., 2006).
These insoluble catalysts are then removed by
filtration.
3.2.2. Direct esterification of fatty acids or methyl esters alcoholysis
PEG has two equivalent reactive OH groups able to be
substituted by a carboxylic acid function. The esterification
therefore results in a mixture of monoesters and diesters. The
scheme of the esterification reaction is presented in Fig. 6.
Reactors used for the esterification 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 sufficient 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
finished 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 difficult to eliminate. Zeolites have been compared
with classical homogenous catalyst p-toluenesulfonic acid (PTSA)
in esterification 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 esterification of fatty acid
methyl esters with PEG is shown in Fig. 7.
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 Pale-yellow waxy
solid
Caprylocaproyl
polyoxylglycerides
C8:0 and C10:0/medium chain triglycerides from coconut oil or hydrogenated palm
kernel oil
200–400 Pale-yellow oily
liquid
Lauroyl polyoxylglycerides C12:0/coconut oil or hydrogenated palm/palm kernel oil 300–1500 Pale-yellow waxy
solid
Stearoyl polyoxylglycerides C18:0/hydrogenated palm oil 300–4000 Pale-yellow waxy
solid
Oleoyl polyoxylglycerides C18:1/apricot kernel oil 300–400 Amber oily liquid
Linoleoyl polyoxylglycerides C18:2/corn oil 300–400 Amber oily liquid
116 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121
9. The reaction is conducted at lower temperature than the
esterification process because the temperature needed to remove
methanol is lower than that required to evaporate water.
Metallic catalyst like sodium shows a high efficacy (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
first 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
transesterification reaction which leads to the formation of
diesters and free PEG (Fig. 8c).
3.3. Critical excipient characteristics: benefits 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 identified
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 specific 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. 5. Alcoholysis/transesterification reaction pathway to manufacture polyoxylglycerides.
Fig. 6. Direct esterification of PEG with free fatty acids.
V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121 117
10. 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-molecular-
weight 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 specifications fall within a
range. Likewise, in the case of the direct esterification 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. 90–99% of a single component) are produced
industrially. This purification step result in a single component
free of unsaturated or unsaponifiable matters (Formo, 1982).
Following hydrolysis of the oil, the fatty acids are purified by
distillation. The use of these high purity products can help
minimize variability in the
final 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. 7. Alcoholysis of fatty acid methyl esters with PEG.
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 Transesterification of PEG monoesters, formation of PEG diesters and free PEG under alkaline conditions.
This ethoxylation process, as well as the esterification of fatty acids with PEG, results in a mixture of PEG monoesters, PEG diesters, and free PEG.
118 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121
11. Oxidative risks may be prevented by measures like the addition
of anti-oxidants, working under vacuum and/or nitrogen blanket-ing
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) verified 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 (OCH2CH2OH)
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
flush is provided after the opening. Other
phenolic compounds used as antioxidants for PEG have been
described (Lloyd, 1961).
The influence 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 hydrogenosulfite (NaHSO3). Sodium meta-bisulfite
(Na2S2O5) in aqueous solutions acts as an oxygen
scavenger and avoid the formation of hydroperoxides, precursors
of formaldehyde, formic acid or macro-aldehydes like PEG-aldehydes
(Hemenway et al., 2012). The purified 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).
Table 6
Critical excipient characteristics for polyoxylglycerides.
Excipient
characteristics
CQA Critical process parameters Impact on
Processability Chemical stability In vivo functionality
PEG composition
Low molecular mass
(600 Da)
No – Liquid
Dispersibility
Chemical reactivity
Hygroscopy
Solubility enhancement
PEG composition
High molecular mass
(1000 Da)
No – Solid (polymorphism)
Hydration time
–
Controlled release
PEG esters composition
Free PEG
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
and packaging
–
#
Oxidative stability
Chemical reactivity
–
PEG impurities
Alkaline impurities
Yes - Neutralization/Filtration step
Dispersibility
Chemical reactivity
Solubility enhancement
#
Controlled release
Fatty acid composition See Table 4
V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109–121 119
12. 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 lipid-based
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
finally the refining steps eventually implemented
(deodorization, neutralization and
filtration).
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