International Journal of Pharmaceutics 466 (2014) 109121

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International Journal of PharmaceuticsPolyoxylglycerides and glycerides: Effects of manufacturingparameters on API stability, excipient functionality and processing

Vincent Jannin a,*, Jean-David Rodier a, Jasmine Musakhanian b

aGattefoss SAS, 36 chemin de Genas, Saint-Priest cedex 69804, FrancebGattefoss Corporation, Plaza I, 115 West Century Road Suite 340, Paramus, NJ 07652, USA

A R T I C L E I N F O

Article history:Received 10 January 2014Received in revised form 13 February 2014Accepted 2 March 2014Available online 05 March 2014

Keywords:Lipid-based excipientPolyethylene glycol esterCritical quality attributeDrug stabilityOxidationChemical reactivity

A B S T R A C T

Lipid-based formulations are a viable option to address modern drug delivery challenges such asincreasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), orsustaining 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 excipientsused by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and morecommonly used in pharmaceutical drug products but there is still a lack of understanding of how themanufacturing processes, processing aids, or additives can impact the chemical stability of APIs withinthe drug product.In that regard, this review summarizes the key parameters to look at when formulating with lipid-basedexcipients 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 theextraction and renement processes. Then, the key parameters during the manufacturing processinuencing the quality of lipid-based excipients are provided. Finally, their critical characteristics arediscussed in relation with their intended functionality and ability to interact with APIs and othersexcipients within the formulation.

2014 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Nature of lipids/excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2.1. Glycerides denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2. Natural sources of lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.3. Extraction and renement of lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.4. Manufacture of lipid excipients glycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2.4.1. Interesterication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.4.2. Esterication, fat splitting, and transesterication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2.5. Critical excipient characteristics: benets and interactions with other components in drug products . . . . . . . . . . . . . . . . . . . . . . . . . . 63. Polyoxylglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

3.1. Nature of excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.2. Manufacturing processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3.2.1. Alcoholysis of triglycerides with PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.2.2. Direct esterication of fatty acids or methyl esters alcoholysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.2.3. Ethoxylation of fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3.3. Critical excipient characteristics: benets and interactions with other components in drug products . . . . . . . . . . . . . . . . . . . . . . . . . . 94. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

* 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.2014.03.0070378-5173/ 2014 Published by Elsevier B.V.

journal homepage: www.elsev ier .com/locate / i jpharm

1. Introduction

Lipid excipients have a wide range of applications inpharmaceuticals, food and consumer products. Liquid glyceridesare commonly used as solubilizers for lipophilic active pharma-ceutical ingredients (API) whereas semi-solid and solid glyceridesserve as matrix formers in sustained release tablets and capsules(Barthlmy et al., 1999; Jannin et al., 2006); as processing aids inthe formation of dispersions or multi particulate systems (Janninet al., 2003; N0Diaye et al., 2003); and as coatings for taste masking,prolonged release or lubrication (Jannin and Cuppok, 2013; Patilet al., 2011). Polyoxylglycerides on the other hand are utilized assolubility 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 aphysical-chemical versatility which is inherently linked to thenature of the lipid moieties which constitute these excipients.

Lipids (fats and oils) are generally dened by their polarity andability to interact with aqueous media, properties conditioned by

enhanced product differentiation or functionality while at thesame time being classied within the same general Pharmacopoe-ial monograph. Even if, lipid-based excipients are more and moreroutinely used there is still a lack of understanding of howexcipient manufacturing processes either directly or indirectly can impact the drug product stability.

Hence, this review aims to elucidate the key parametersinuencing two groups of lipid excipients: glycerides, being fattyacids esters of glycerol and polyoxylglycerides being fatty acidesters polyethylene glycol (PEG) and glycerol presented in twoseparate sections. The rst section starts by an introduction to thechemistry of natural lipids (fats and oils), fatty acids and theirproperties in relation to the extraction and renement processesused. In addition, the critical characteristics of these excipients ontheir functionality and ability to interact with other materials anddrug substances will be discussed.

2. Nature of lipids/excipients

c

110 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121their composition. Fatty acids are the single common denominatorin all lipids. The functionality of lipids is linked to their structuralmoieties, notably the type of fatty acids and their esters present.Fatty acids are abundant in nature, found notably in dietary lipidsin the form of glycerides (fatty acid esters of glycerol). Glyceridesand their fatty acid components serve as building blocks for themanufacture of lipid excipients. Depending on the intendedcharacteristics of the nal excipient, manufacturing may involvea complex series of processes such as fractionation, esterication,inter-esterication, alcoholysis, and multiple purication steps.The functionality of the end product in the pharmaceutical dosageform is therefore inherently linked to the source of the rawmaterials and the manufacturing processes. Precise control ofcomposition and characteristics of lipid based excipient is essentialfor their subsequent use as a pharmaceutical excipient. However,these excipients can contain impurities that often contributesignicantly 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 themanufacturing processes of lipid-based excipients on the stabilityof pharmaceutical dosage forms manufactured. Variations ofcomposition of these excipients deriving from natural products,the potential presence of process aids, additives, and/or stabilizersadded during their extraction, rening, and processing canprofoundly impact the stability of the API in dosage forms madeusing one or more of such excipients. In addition, different gradesof these lipid-based excipients have been introduced to provide

Fig. 1. Structures of acylglycerols: a. triacylglycerol; b. 1,2-diacylglycerol;2.1. Glycerides denition

Glycerides are the primary components of dietary lipids (fats andoils). Lipids are fattyacidsand theirderivatives, and substances relatedbiosynthetically or functionally to these compounds (Christie, 1987).Lipids are amphiphilic due to their dual molecular structure i.e. thelipophilic portion consisting of fatty acid(s) and the hydrophilicportion to which the fatty acid(s) are esteried (glycerol in the case ofglycerides) (Jannin et al., 2008). They can be divided in two groupsdepending on their interaction with water (Larsson et al., 2006).

The rst group relates to non-polar lipids that are non-misciblewith water. Oils and fats are mainly composed of triacylglycerols(also known as triglycerides) and are the main components of thisgroup. Triacylglycerols are composed of three fatty acids (acylgroups) esteried to glycerol (see Fig. 1). Their partial glyceridesderivatives: diacylglycerols (diglycerides) are also non-polar.Diacylglycerols are composed of two fatty acids esteried toglycerol. Each diacylglycerol molecule exists as two differentisomers: 1,2- and 1,3-position. The migration of fatty acid from oneposition to another is favored by temperature (even at roomtemperature for liquids) and the equilibrium mixture is reached.

The second group consists of polar lipids that can interact withwater to form aqueous phases. Monoacylglycerols (monoglycer-ides) is one example of polar lipids. They can exist as two isomersas 1- (which is equivalent to the 3-) and 2-position. The 1-isomer islargely predominant in the equilibrium mixture reached after acylmigration.

. 1-monoacylglycerol. The fatty acid used for this gure is stearic acid.

Since dietary lipids are the principal source of glycerides, thebuilding blocks for lipid excipients, a review of the currentpractices that yield dietary lipids is necessary. The next section

whereas fat is applied to solid or semi-solid glycerides. Fatsshould not be confounded with solid waxes which arechemically different from glycerides; they are esters of fatty

Table 1Nomenclature 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 16.5Capric acid 10:0 CH3(CH2)8COOH 31.6Lauric acid 12:0 CH3(CH2)10COOH 44.8Myristic acid 14:0 CH3(CH2)12COOH 54.4Palmitic acid 16:0 CH3(CH2)14COOH 62.9Stearic acid 18:0 CH3(CH2)16COOH 70.1Oleic acid 18: 1 (9c) CH3(CH2)7CHQCH(CH2)7COOH 16.0Ricinoleic acid 18: 1 (9c), OH (12) CH3(CH2)5CHOHCH2CHQCH(CH2)7COOH 5.5Linoleic acid 18: 2 (9c12c) CH3(CH2)4CHQCHCH2CHQCH(CH2)7COOH 5.0Linolenic acid 18: 3 (9c12c15c) CH3CH2CH=CHCH2CHQCHCH2CHQCH(CH2)7COOH 11.0Eicosenoic 20:1 (11c) CH3(CH2)7CHQCH(CH2)9COOH 23.0Behenic acid 22:0 CH3(CH2)20COOH 80.0Erucic acid 22:1 (13c) CH3(CH2)7CHQCH(CH2)11COOH 33.8a 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.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121 111therefore discusses the key processing steps and the potentialimpact they may have on the composition and quality of therened lipids; considerations for selection of the natural source ofthe lipids; and the principal differences in fatty acid structure andcomposition.

2.2. Natural sources of lipids

Lipids may be obtained from animal or vegetable source. Thediscussion herein is limited to vegetable oils given the abundance,variety, safety, and overall preference by the pharmaceuticalindustry.

Vegetable oils are obtained either from seeds, kernels, orfruits. Each of these species has its unique composition andrepartition of fatty structures in terms of hydrocarbon chainlength and the number of unsaturated bonds in the chain. Thesestructural variations impact the physical properties of theglycerides. The melting point of glycerides, for example, riseswith increasing hydrocarbon chain length but drops withincreasing number of double bonds otherwise referred to asdegree of unsaturation. Generally, the term oil is used todescribe glycerides that are liquid at or above room temperature

Table 2

Fatty acid composition of some vegetable oils used in the pharmaceutical industry (M

Vegetable oils Caprylicacid

Capricacid

Lauricacid

Myristicacid

Palmiticacid

Stearicacid

Oils from seeds and kernelsSunower oil 57 46 Soybean oil

112 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 1091212.3. Extraction and renement of lipids

Industrial operations involved in the processes from harvestto extraction and renement of vegetable oils necessitatemultiple transfers to different processing locations. Thefollowing section summarizes two main trituration schemes(Fig. 2), applied to the extraction of oils from either seeds orfruits (Laisney et al., 1992). The discussion that follows willfocus mainly on the steps that inuence the nal quality of thenal product.

The trituration of seeds starts by a cleaning step using sievesand magnets to remove dust, husks and iron impurities due toharvesting. The seeds are then dried to reduce their water contentto 58%, which favors the safe storage of seeds and facilitates thesubsequent shelling, to separate the seed from the hull. The seedsare then ground and attened with a rotating cylinder or grinderand then heated to further reduce the water content of seeds;increase their plasticity and uidity; coagulate the proteinscontained in the seeds; reduce the bioburden (by destroyingbacteria for example); deactivate thermo sensitive enzymes; andeliminate thermo sensitive toxic substances. The bulk of the oil ispressed out using either hydraulic presses (pressure ranging from 4to 500 bars) or screw presses in a continuous process. A ltration orcentrifugation step can follow to clarify the oil. An additionalheating step at 8090 C under vacuum to dehydrate the oil downto 0.1% of water may be applied and the residual oil remaining inthe seeds may be removed by chemical extraction. The latterapproach is faster, facilitates a higher yield and signicantlyreduces cost. After the extraction step, the organic solvent iseliminated with residual content of no more than 300 ppm left

Fig. 2. Trituration steps to obtain oils from seeds and fruits.behind.For fruits, trituration starts by washing with water to remove

leaves and other impurities. In the case of palm fruits a heatingstep and picking off (substep removing fruits from the bunch) areadded to deactivate lipases that would otherwise go onconverting glycerides into glycerol and fatty acids. The fruitsare 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 phaseconsisting of oil and water that can be separated by decantationor centrifugation to obtain virgin oil in the case of olive. In somecases the pressing step can be replaced by a centrifugation of thepaste with water. Finally a ltration step either through a paperlter or using ltration (adsorbing) earth could be implementedto clarify the oil.

After trituration, oils are composed mainly of 9095%triacylglycerols. They also contain some minor components thatcan have signicant impact on the quality of the nished oil. Theseinclude (Jannin et al., 2008):

Free fatty acids present in the seed or produced during theextraction or storage of the oil through hydrolysis of acylglycerols.Free fatty acids (unsaturated or not) are catalysts to the hydrolysisof triacylglycerols leading to increased levels of partial glycerides.

Water the quantity of water in oil should be below 0.2% reducethe hydrolysis of acylglycerols.

Partial glycerides diacylglycerols and monoacylglycerols areformed during the hydrolysis of triacylglycerols. Monoacylgly-cerols are amphiphilic and can emulsify the oil with water duringthe rening of oil impacting process efciency.

Phospholipids amphiphilic molecules like lecithin can limit theefciency of the rening process. Phospholipid quantities mayvary from nearly zero in palm oil to 2% in soybean oil.

Colorants coloring agents such as b-carotene, chlorophyll andother agents may be released due to the oxidation of the oilduring the extraction and rening processes.

Sugars present in the seed that serve to produce glycerol andfatty acids.

Hydrocarbons either naturally present in oils (like squalene) orformed during the extraction of oil from seeds with hexane.

Tocopherols also known as vitamin E, tocopherols are naturalantioxidants which provide natural chemical stability for oils. Withthe exception of palm kernel and coconut oil that mainly consist ofsaturated fatty acids, all vegetable oils contain tocopherols inquantitiesrangingfrom200to1200 ppm(SoulierandFarines,1992).

Other sterols, waxes, metals, aldehydes, ketones, and toxins,can either be naturally occurring in some plants (gossypol incotton seed oil) or introduced by fungi to the crop (fungalaatoxins), or by articial additives like pesticides or insecti-cides. These toxins are eliminated during renement.

Rening of crude oils helps remove many undesirablecomponents; 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 theconcentration of triacylglycerols (>99%) (Denise, 1992):

Deacidication: Also referred to as neutralization is carried outto eliminate all free fatty acids. It is achieved either by chemical(addition of sodium hydroxide) or physical means (vaporstriping). The chemical method has unique advantages as italso eliminates sugars (mucilage that precipitate in presence ofalkali), metals, and toxic substances (gossypol, aatoxin, andorganophosphate insecticides).

Washing of oils with water eliminates amphiphilic molecules(phospholipids, monoacylglycerols, and soaps formed during thedeacidication step) after decantation.

Bleaching of oils is conducted with adsorbing earths or activatedcarbon.

Deodorization of oils is carried out in presence of heat and undervacuum to remove all volatile components including hexane. Atthe end of this step the residual content of hexane should bebelow 1 ppm. Water may be introduced to the bottom of the oilvessel which readily boils off as steam, removing all watersoluble impurities. The process can also eliminate peroxides bythermal degradation, some molecules responsible for taste andsmell such as aldehydes or ketones, some toxic organochlorideinsecticides, and part of the tocopherols.

2.4. Manufacture of lipid excipients glycerides

Triacylglycerols can be used in their native form for nutritionalor pharmaceutical purposes. The development and manufacture of

unique and specialized lipid excipients however necessitatesmodications and improvements to either fatty acid distributionor degree of esterication to the glycerol molecule. A number ofprocesses are described below.

and Table 3 summarizes information on the main catalysts andconditions of use.

2.4.2. Esterication, fat splitting, and transestericationPartial glycerides (mono- and diacylglycerols) are commonly

used as pharmaceutical excipients. They are obtained mainly bytwo processes: esterication or transesterication (Sonnet, 1999;Sonntag, 1982a).

Esterication is a reaction where selected fatty acids arerecombined with glycerol. Free fatty acids are obtained through afat splitting step that entails the hydrolysis of oils to yield free fattyacid and glycerol. These hydrolysates are then distilled to obtainfatty acids of specic chain length which are subsequentlyesteried anew with glycerol at a predened ratio to obtain theintended partial glycerides. The process is commonly used tosynthesize medium chain triglycerides from coconut oil forexample.

Fig. 3. Reaction scheme of the interesterication process with a reactiontemperature of 90 C and sodium methylate as catalyst.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121 1132.4.1. InterestericationNew glycerides may be prepared by redistribution of the fatty

acids on the glycerol backbone or by the combination of twotriglycerides by a process known as interesterication. Fig. 3 showsthe composition of a new glyceride obtained from the interester-ication of two pure triacylglycerols (AAA and BBB).

Prior to the interesterication, product AAA consists only offatty acid A in all three ester positions. Triacylglycerol BBB, on theother hand, consists of fatty acid B in all three positions. Afterinteresterication new acylglycerols are formed with combina-tions of fatty acids A and B in all positions.

Interesterication of oils or oil mixtures enables the redistri-bution of the fatty acids on the glycerol backbone. The processimproves the homogeneity of triglyceride molecules in terms offatty acid composition; it helps improve or control the physical(melt) characteristics of oils/oil mixtures. It does not however alterthe degree of unsaturation or isomeric state of the starting product.

Interesterication reaction may be driven by chemicals orenzymes. The reaction can be conducted at high temperatures(250 C or more) or alternatively at lower temperatures inpresence of catalysts. Inert gas is invariably applied duringinteresterication to prevent coloration of the mixture. Thecatalysts 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). Themechanism of interesterication using CH3ONa is well describedin the literature (Liu, 2004). This reaction should be conductedunder inert gas to avoid coloration of the mixture. Many othercatalysts and conditions have been described (Sreenivasan, 1978),

Table 3List of main catalysts used for interesterication and conditions of use.Catalyst Percentage ofuse/reactiontemperature

ReactionTime(min)

Advantages

Metal alkylatee.g. sodium methylate(CH3ONa)

0.12%50120 C

50120 Cost, ease of handling (drypowder), low level of use (0low temperature

Sodium-potassium alloy(NaK)

0.051%25270 C

3120 Liquid, easy to handle, highreactive, short time reactio

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

0.050.1%140160 C

90(vacuum)

Cost, easy to handle as anaqueous solution

Sodium hydroxide (NaOH) 0.52%250 C

90(vacuum)

Cost, easy to handle as anaqueous solutionFat splitting can be achieved in many ways including:saponication of oil i.e. reaction with a strong alkali, autoclavingwith a catalyst, high-pressure countercurrent splitting, or enzy-matic degradation. The range of temperature used for splitting is150260 C. Fat splitting is a homogeneous reaction involvingdispersion of water in the oil phase. The reaction is slow at theonset because water has low dispersibility in triacylglycerols butincreases as di- and monoacylglycerols are formed until anequilibrium between free fatty acid and glycerol is reached. Topush the reaction further, the free glycerol must be removed fromthe reaction. Fat splitting is accelerated by mineral acids, metaloxides, mainly zinc and magnesium oxides that form liposolublesoaps that in turn drive the emulsication of oil with water andspeed up the process.

Esterication is the reverse reaction to fat splitting. Fatty acidsand 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, andcommon catalysts include acid catalysts, sulfonic acids, zinc or tinmetals. Acid catalysts often darken the product and can lead to thedehydration of unreacted glycerol to yield acrolein. In the absenceof a catalyst the reaction must be carried out at a temperatureabove 250 C, which enables a reaction speed equivalent to thatobtained with a catalyst (Sonntag, 1982a).

Glycerolysis is a transesterication process in which triglycer-ides are reacted with glycerol to yield partial glycerides. Theprocess must be conducted in a reactor with efcient agitationbecause glycerol and oil are not miscible during the early stage ofthe reaction. Sodium hydroxide is often used as a catalyst andforms soaps that promote the reaction by increasing the solubilityof glycerol in the oil phase. High processing temperature

Disadvantages Removal of the catalyst

.1%),Loss of oil with theformation of methyl estersand soaps

Removal of the catalyst and soaps by acidneutralization and water washing (Ahmadiet al., 2008).

lyn

Very reactive with waterand hydroxyl group,hydrogen formation

Deactivation with water.Removal of soaps by washing

Formation of partialglycerides

Neutralization of the catalyst with phosphoricacid, removal of salts by washing with water(Hurtova et al., 1996)

Higher reactiontemperature, coloration ofthe product

Removal the soaps by washing

(200250 C) is required in order to decrease the reaction time andto increase the miscibility of oil with glycerol (Sonntag, 1982a,1982b).

2.5. Critical excipient characteristics: benets and interactions withother components in drug products

The most important or critical characteristics of glycerides(Table 4) are structure of fatty acid(s), degree of saturation andchain length, mono- and diglycerides content, and the presence ofnatural antioxidants and or impurities. Among these character-istics we identied the critical quality attributes (CQA) ofexcipients linked to the critical process parameters (CPP).

Fatty acid composition in naturally occurring lipids is denedby the plant origin, i.e. species (see Table 2), variety or cultivar (forexample. high-oleic acid sunower low-erucic acid rapeseed(Merrien, 1992; Morice, 1992)), geography/location, seasons,temperature and rainfall (Richards et al., 2008). For syntheticglycerides, fatty acid composition is controlled to different degreesby the manufacturing process parameters as described inSection 2.4. In addition to the nature of fatty acids, the ratio ofmono-, di- and triesters is the second most important parameterdening the functionality of glycerides (Prajapati et al., 2012;Witzeba et al., 2012).

The functionality of glycerides can be explained by the varyingroles they can play in drug delivery: as inert drug carriers for llinginto hard or soft shell capsules (e.g. medium and short chaintriglycerides); solubilizers for highly lipophilic drugs possessinghigh Log P (long chain glycerides); by rate of digestion (fastest withthe shortest fatty acid chain length); by rate and degree of drug

In the case of solid-phase glycerides, the crystalline structureof the molecules can add a new dimension to excipientfunctionality, notably in relation to their ability to control drugrelease (Hamdani et al., 2003). Aside from melt characteristics, allsolid-phase glycerides exhibit polymorphism. Hard fat triglycer-ides exhibit polymorphism with a monotropic evolution, leadingto denser and more stable polymorphs over time and tempera-ture. Predicting such changes can help optimize the formulationparameters to achieve a desired drug release prole. Monogly-cerides on the other hand, have an enantiotropic polymorphismwhereby the most stable crystalline form changes reversibly as afunction of temperature, thus having little impact on drug releasein physiological conditions. Mixtures of glycerides exhibit a morecomplex polymorphism depending on the relative quantity ofeach esters and fatty acids (Gunstone and Padley, 1997; Small,1986). Lipid polymorphism can be readily controlled by adaptedthermal treatments (Brubach et al., 2007) or by formulationdesign.

Glycerides and more specically triacylglycerols are inertentities with high compatibility with many commonly usedexcipients. Glycerol esters containing saturated fatty acids aremostly inert and naturally protected against oxidation. In the caseof unsaturated fatty acid esters, sensitivity to oxidation increaseswith the degree of unsaturation (number of double bonds) whereoxidation can occur if left unprotected. Oxidation inherentlyinvolves free radicals and auto-oxidation, and reactivity can belimited by the natural presence of antioxidants in the crude orvirgin oil but accelerated in the presence of trace metals (Janninet al., 2008).

Auto-oxidation is the direct reaction of oxygen with the fatty

114 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121micellization in vitro (Williams et al., 2012) and in-vivo due tolipolysis (faster with partial glycerides or medium short chain fattyacid esters); and mode of uptake into systemic circulation hepaticvs. lymphatic the latter being slower, longer, and limited to longchain glycerides.

Table 4Critical excipient characteristics for glycerides.

Excipientcharacteristics

CQA Critical process parameters (CPP)

Fatty acid chain lengthMedium chain

No

Fatty acid chain lengthSaturated long chain

No

Fatty acid chain lengthUnsaturated longchain

No

Glycerides compositionHydroxyl groups

Yes - Oil/glycerol ratio in the mixture- Temperature and duration of synthesis- Amount of catalysts

Minor componentsNatural antioxydants

No

Minor componentsFree fatty acids

Yes - Temperature and duration of synthesis- Deodorization step

ImpuritiesMetal content

No

ImpuritiesPeroxides, aldehydes

Yes - Nitrogen blanketing during synthesisand packaging

ImpuritiesSoaps, alkalineimpurities

Yes - Type of catalysts- Neutralization/Filtration stepacid chain, and many parameters can induce this process whichoccurs in three stages (Frankel, 2005a):

Initiation the rst step of oxidation of the unsaturated fattychain is the formation of a free radical by the action of an

Impact on

Processability Chemical stability In vivo functionality

Liquid " " Solubilityenhancement" Paracellularpermeability

Solid(polymorphism)

" " Controlled release# Digestibility

Liquid # Oxidative stability " Solubilityenhancement of highLogP drugs" Lymphatic uptake

# Lipophilicity" Dispersibility

" Chemical reactivity " Solubility by physicaldrug inclusion (Chawlaand Saraf, 2011)

" Oxidative stability

" Chemical reactivity

# Oxidative stability" Chemical reactivity

# Oxidative stability" Chemical reactivity

" Dispersibility " Chemical reactivity " Solubilityenhancement# Controlled release

initiator. The initiator may be the dissociation of hydroperoxideby action of temperature, light or metals.

Propagation radicals react with oxygen and produce newhydroperoxides. Oxygen reacts selectively with allylic hydrogensto form hydroperoxides.

Termination recombination of two radicals to form non-radicalproducts.

Hydroperoxides can react with API or other excipients andoxidize them. The allylic hydrogens play an important role duringthis oxidation process. The more double bonds are contained in afatty acid chain, the more oxidation occurs in the product, as suchthe oxidation rate of polyunsaturated fatty acids (PUFA), is greaterthan monounsaturated ones. For example, auto-oxidation ofmethyl linoleate is 40 times greater than methyl oleate, due to

Some pharmaceutical preparations may be sensitive to freehydroxyl groups (monoglycerides > diacylglycerols > triacylglycer-ols) thus hydroxyl value. In the manufacture of suppository basesfor example, hydroxyl value may be a key parameter inuencingthe rate of crystallization/solidication of pessaries. In thepresence of heat, there is also potential for some ingredients orAPI to react with the free hydroxyl groups of the glycerides.Formulations that are sensitive to such reactions therefore requireexcipients with lowest possible hydroxyl value.

Whenever catalysts are used in the manufacturing of syntheticglycerides, a neutralization step and subsequent removal of thecatalysts are carried out. The efciency of the neutralization andremoval of the residual alkaline impurities is assessed by analkaline impurities test with allowable limits well below 50 ppmNaOH with as low as 0 ppm Na OH.

yoxy

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121 115the presence of a methylene (CH2) group entrapped betweentwo double bonds (Frankel, 2005b).

Hydroperoxides split up into degradation products following ahomolytic b-scission. This mechanism, inuenced by temperatureand metals as catalysts, leads to the formation of various organicdegradation 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 obtainedby dimerization of hydroperoxides, oxidized esters, oxidizedfatty acids, and core aldehydes (high molecular weightoxoglycerides).

Plant lipids are naturally protected against oxidation due topresence of tocopherols (Frankel, 2005d) in quantities rangingfrom 200 to 1200 mg/kg in non-rened state (Soulier and Farines,1992). Their presence in oils and fats is always benecial to theoxidative stability of API (Takahashi et al., 2003), but the reningprocess can reduce drastically their content. Therefore, dependingon the natural variability of oil and the production parametersdescribed 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 practicereserved mainly for oils destined for the food market. Pharmaceu-tical grade raw materials do not contain additives and protectedagainst oxidation merely by process and packaging controls. Iodinevalue (degree of unsaturation), peroxide value (measure ofoxidative species present) and acid value (measure of free fattyacids) are examples of controls relating to the quality of glyceridesand lipid excipients in general.

Fig. 4. Chemical structures of PEG esters comprised in pol3. Polyoxylglycerides

3.1. Nature of excipients

Polyoxylglycerides (macrogolglycerides in the European Phar-macopeia) are complex excipients obtained by reacting glycerideswith polyoxyethylene glycols (PEG). The process yields mixtures ofmono-, di-, and triacylglycerols (Fig. 1) and mono- and diesters ofPEG (Fig. 4).

Whereas processing parameters have signicant impact on theend product, the raw material (glycerides and PEG) properties arearguably most crucial dening the molecular make up and thusthe physical-chemical behavior of polyoxylglycerides. Glyceridesare discussed in the previous section and before delving into themanufacture and critical aspects of polyoxylglycerides, a shortdiscussion of PEG in this section is necessary.

Polyoxyethylene glycols (PEG) or polyethylene oxides (macro-gols in the European Pharmacopoeia) are polymers of ethyleneoxide with the following structure: HO(CH2CH2O)nH. PEGare identied by a number which may stand either for the averagenumber of ethylene oxide units or for the mean molecular weightof the polymer. For example a PEG with 32 ethylene oxide unitspossesses a molecular weight of 1500 Da and could be identiedeither as PEG-32 or PEG 1500. PEGs with molecular weight below600 Da are viscous liquids and above 1000 Da are solids at roomtemperature. All PEGs are freely soluble in water.

The denition of polyoxylglycerides in the compendia howeveris not always as pointed and at times a single monograph mayencompass a range of polyoxylglycerides. Table 5 presents themonographs listed in the current edition of USP-NF for polyox-ylglycerides.

Each of the polyoxylglyceride monographs may cover a range ofexcipients depending on the type of PEG and the ratio of glyceridesto PEG used in the manufacturing process. For example, the lauroyl

lglycerides: a. PEG-8 monocaprylate. b. PEG-8 dicaprylate.

(H

co

el

116 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121polyoxylglycerides monograph indicates PEGs with molecularweights ranging from 300 to 1500 Da. Two currently marketedexcipients fall in this category involving PEG 300 (PEG-6) or PEG1500 (PEG-32). These excipients possess different surfactantproperties due to the length of their PEG moieties. Lauroylpolyoxyl-6 glycerides have a hydrophilic-lipophilic balance (HLB)value of 9 whereas lauroyl polyoxyl-32 glycerides possess an HLBof 11. Another major difference between two polyoxylglycerides,apart from the size of the PEG moiety, can be in the amount of freePEGs present, which is dependent on the ratios of the rawmaterials used during the reaction, wherein an excess of PEG favorsthe production of PEG esters.

Polyoxylglycerides can be manufactured by three differentprocesses:

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 partialglycerides).

3.2. Manufacturing processes

Polyoxylglycerides can be obtained either by an alcoholysis/transesterication of lipids by polyoxyethylene (PEG) or by mixingPEG esters with glycerides. The nature of glycerides and theirproduction is presented in Section 2. This section describes thealcoholysis/transesterication reaction pathway followed by themanufacturing process of PEG esters.

Industrial transesterication or esterication reactions arecarried out in carbon-steel or stainless-steel reactors. Estericationreaction is generally preferred as a batch process rather than as acontinuous one because of the long reaction times and the quantity

Table 5Polyoxylglycerides listed in the USP-NF.

USP-NF monograph Main fatty acid/vegetable oil source

Behenoyl polyoxylglycerides C22:0/hydrogenated high erucic acid rapeseed oil

Caprylocaproylpolyoxylglycerides

C8:0 and C10:0/medium chain triglycerides from cokernel oil

Lauroyl polyoxylglycerides C12:0/coconut oil or hydrogenated palm/palm kern

Stearoyl polyoxylglycerides C18:0/hydrogenated palm oil

Oleoyl polyoxylglycerides C18:1/apricot kernel oil Linoleoyl polyoxylglycerides C18:2/corn oil of water to be removed during the reaction (Hasenhuettl, 2000).

3.2.1. Alcoholysis of triglycerides with PEGThe raw materials, oils (triglycerides) and PEG, are introduced

in the reactor before the addition of a catalyst (generally an alkalinehomogeneous catalyst is used). The reaction is conducted at hightemperature under inert gases like nitrogen or under vacuum tolimit the introduction of oxygen and to avoid oxidative reactions.After completion of the reaction, the catalyst is neutralized, and themedium cooled down. The neutralized catalyst generally forms asalt that is removed by a separation step such as ltration. Thereaction scheme is presented in Fig. 5.

The reaction pathway yields a complex mixture of triglycerides,partial glycerides (mono- and diacylglycerols), PEG fatty acidsmono- and diesters, free glycerol and unreacted PEG andtriacylglycerols (Hamid et al., 2004).The alcoholysis reaction described in Fig. 5 shows therearrangement of the positioning of the fatty acids on the glycerolmolecule. Homogeneous catalysts (soluble in the reaction mixture)such as hydroxide, methoxide or alkali metal can be used. Thisprocess requires a neutralization step and then the removal of saltsby ltration. The use of heterogeneous catalyst (insoluble in thereaction mixture) to produce PEG fatty esters by transestericationof 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 alcoholysisPEG has two equivalent reactive OH groups able to be

substituted by a carboxylic acid function. The estericationtherefore results in a mixture of monoesters and diesters. Thescheme of the esterication reaction is presented in Fig. 6.

Reactors used for the esterication of fatty acid with PEG aresimilar to those described for glycerides in Section 2.4. Fatty acidsand PEG are mixed together in a reactor. A catalyst can be added tothe medium to accelerate the reaction. The reactor contents areheated to a temperature sufcient to activate the reaction. Watercan be partially eliminated by heat and by the application of inertgas (nitrogen) or vacuum.

The reaction products are a mixture of mono- and diesters ofPEG. The ratio of the monoesters/diesters in the nished productdepends on the initial ratio of the raw materials, PEG/fatty acids.Using a large excess of PEG over fatty acids leads to a high amountof monoesters. PEG/fatty acid ratios of 6 to 12 are described formanufacturing products with high monoesters content (Weil et al.,1979). These conditions however produce also a high amount ofunreacted PEG. Thus, a higher ratio of monoesters/diesters isassociated with lower production yield after removal of the freePEG.

Homogenous catalysts are often used to improve the process bydecreasing the reaction temperature and time. Acids are often used

Molecular weight of PEGused

Physical appearance

EAR) 400 Pale-yellow waxysolid

nut oil or hydrogenated palm 200400 Pale-yellow oilyliquid

oil 3001500 Pale-yellow waxysolid

3004000 Pale-yellow waxysolid

300400 Amber oily liquid300400 Amber oily liquidas catalysts: p-toluenesulfonic acid, sulfuric acid, phosphoric acid(Weil et al.,1979). Novel catalysts have been studied to increase theselectivity of monoesters without using a large excess of PEG,which is then difcult to eliminate. Zeolites have been comparedwith classical homogenous catalyst p-toluenesulfonic acid (PTSA)in esterication reaction between oleic acid and PEG 600 (Hamidet al., 2004). The study shows a superior selectivity of the zeolitesto form PEG monoester compared to PTSA. Another recentlydescribed process condition involves the use of high ratio of PEG/fatty acid (10:1) combined with a supported enzyme (Novozym435) as catalyst (Viklund and Hult, 2004). The unreacted PEG isremoved by repeated extraction using NaCl solution and ethylacetate. The reaction leads to a monoesters content between 77%and 87%.

The second alcoholysis pathway for esterication of fatty acidmethyl esters with PEG is shown in Fig. 7.

on p

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121 117The reaction is conducted at lower temperature than the

Fig. 5. Alcoholysis/transesterication reactiesterication process because the temperature needed to removemethanol 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 ofalkali metals are the most commonly used.

3.2.3. Ethoxylation of fatty acidsThe 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 acidsto form carboxylates. The carboxylates are then reactedwith ethylene oxide. Initially, all of the fatty acids are consumedto form ethylene glycol monoesters (Fig. 8a), followed bypropagation of ethoxylation (Fig. 8b). As the reaction continuesunder alkaline conditions, monoesters become engaged in a

Fig. 6. Direct esterication of transesterication reaction which leads to the formation of

athway to manufacture polyoxylglycerides.diesters and free PEG (Fig. 8c).

3.3. Critical excipient characteristics: benets and interactions withother components in drug products

Polyoxylglycerides are complex excipients, demonstratingcomplex properties all dependent on the nature of the rawmaterials and the processes used in their manufacture assummarized in Table 6. Among these characteristics we identiedthe critical quality attributes (CQA) of excipients linked to thecritical process parameters (CPP).

An important contributor to variability in polyoxylglycerides isthe inconsistencies in the raw material PEG. In effect, each gradeof PEG has a specic molecular mass distribution with a rangedependent on the manufacturer. The distribution can also bedifferent from batch to batch. PEG may be obtained in a number ofways: interaction of ethylene oxide with water, ethylene glycol, or

PEG with free fatty acids.

ethylene glycol oligomers. Generally, PEGs obtained by thereaction between ethylene oxide and ethylene glycol arepreferred because the reaction leads to a polymer with anuniform weight distribution (Kosswig, 1998) therefore a muchlower polydispersity. PEG are also an important source ofimpurities such as ethylene oxide and 1,4-dioxane or alkalicatalysts such as sodium hydroxide, potassium hydroxide, orsodium carbonate which are used to prepare low-molecular-weight polyethylene glycol.

An important and yet less known aspect of PEG is their highsensitivity to oxidation. The presence of free (unreacted) PEG inpolyoxylglycerides is an important contributor of oxidativesensitivity.

A third parameter of variability in polyoxylglycerides relates to

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 ahigh purity (i.e. 9099% of a single component) are producedindustrially. This purication step result in a single componentfree of unsaturated or unsaponiable matters (Formo, 1982).Following hydrolysis of the oil, the fatty acids are puried bydistillation. The use of these high purity products can helpminimize variability in the nal polyoxylglycerides products.

Direct interactions between polyoxylglycerides and otherexcipients or API, may be formulation dependent. Indirectreactions however may stem from the presence of impuritiescombined with the sensitivity of polyoxylglycerides to oxidation.The susceptibility of polyoxylglycerides to oxidation relates

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

118 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121the composition of oils. Vegetable oils containing a complexcomposition of fatty acids will lead to numerous possiblecombinations between these fatty acids and the different PEGchains. Industrially, it is rare to use triacylglycerols composed ofonly a single fatty acid type. Often oils are composed of variousfatty acids and their individual content specications fall within aFig. 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 underThis ethoxylation process, as well as the esterication of fatty acids with PEG, results generally to the PEG moiety, to the presence of unsaturated fattyacids, and to the presence of the impurities in the excipient andfrom other ingredients in the drug formulation. Polyoxylglycerideimpurities may come from the raw materials themselves, may begenerated during their storage, the production of the excipient, orpost production alkaline conditions.in a mixture of PEG monoesters, PEG diesters, and free PEG.

V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121 119Oxidative risks may be prevented by measures like the additionof anti-oxidants, working under vacuum and/or nitrogen blanket-ing to protect the excipient and the formulation. Other controlsinclude minimizing exposure to heat, aeration, humidity, and light.Simple routine testing for acid value, peroxides, and water contentcan help assess oxidative changes following critical processing andformulation steps.

Following the same scheme as fatty acid auto-oxidation, PEG

Table 6Critical excipient characteristics for polyoxylglycerides.

Excipientcharacteristics

CQA Critical process parameters

PEG compositionLow molecular mass(1000 Da)

No

PEG esters compositionFree PEG

Yes - Lipid/PEG ratio in the mixture- Temperature and duration of synthesis- Amount of catalysts

PEG esters compositionFree fatty acids

Yes - Temperature and duration of synthesis- Deodorization step

PEG esters compositionMonoesters

Yes - Lipid/PEG ratio in the mixture- Temperature and duration of synthesis- Amount of catalysts

PEG impuritiesDioxane

Yes - Type of catalyst (acid catalyst)- Temperature of process- Deodorization step

PEG impuritiesAldehydes, peroxides

Yes - Nitrogen blanketing during synthesisand packaging

PEG impuritiesAlkaline impurities

Yes - Neutralization/Filtration step

Fatty acid composition See Table 4oxidation includes three steps (Kumar and Kalonia, 2006; Lloyd,1961): initiation, propagation, termination.

Studies on polyoxyl derivatives show that a-hydroperoxidesdegrade 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 physicalproperties (cloudy point) veried during these studies suggeststhat the scission occurs on the EO terminal unit and not in the coreof 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). Similarexperiments conducted at 150 C in ambient atmosphere tend to thesame conclusions, as demonstrated by 13C NMR analysis (Mkhatreshand Heatley, 2002). Other studies show that in PEG 400 aqueoussolutions, formaldehyde and formic acid are the major impurities,beside acetaldehyde and acetic acid. The mechanisms by which theseimpurities are formed in accelerated conditions (40 or 50 C in acidicmedia) are described in (Hemenway et al., 2012).

Effects of pro-oxidant such as light and copper sulfate at 40 Con the peroxidation of polyoxyl derivatives have been studied(Hamburger et al., 1975). The induction phase is reduced by thepresence of these pro-oxidants. During the propagation step,peroxide index increases dramatically then drops during thetermination step, traducing the conversion of peroxides intodegradation and terminal products.

Metals like Cu2+ and Fe3+ are strong peroxidation agents (Jaegeret al., 1994). PEG-based products stored in dark conditions orprotected by antioxidant like butylated hydroxytoluene (BHT)maintain a low peroxide index. However the peroxide value ofproducts stored in air-tight container will increase over time(months) unless gases ush is provided after the opening. Otherphenolic compounds used as antioxidants for PEG have beendescribed (Lloyd, 1961).

The inuence of alkali metals (KOH, NaOH) have been studiedon the deformylation of the POE chain in presence of Cu2+

Impact on

Processability Chemical stability In vivo functionality

Liquid" Dispersibility

" Chemical reactivity" Hygroscopy

" Solubility enhancement

Solid (polymorphism)" Hydration time

" Controlled release

" Dispersibility " Hygroscopy " Paracellular uptake (PEG-8)

" Chemical reactivity

" Dispersibility" HLB

" Solubility enhancement

" Toxicity

# Oxidative stability" Chemical reactivity

" Dispersibility " Chemical reactivity " Solubility enhancement# Controlled release(Sakharov et al., 2001). Bases induce deprotonation of PEG andthe anion forms a complex with Cu2+, formic acid is thenproduced. Copper forms a complex with the polyether chain andnot with the terminal hydroxyl groups of the PEG. Thus, thestability of this complex is increased by the length of the PEGchain.

Photo-oxidation studies (light irradiation at 300 nm, 60 C) onPEG moieties also show the hydroperoxide formation on thea-position of the ether bond (Gauvin et al., 1987). Degradationproducts are formiates (formic acid esters). Peroxide can interactwith amino-acids (e.g. cystine) and proteins (Ha et al., 2002). Someoxidative 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 meta-bisulte (Na2S2O5) in aqueous solutions acts as an oxygenscavenger and avoid the formation of hydroperoxides, precursorsof formaldehyde, formic acid or macro-aldehydes like PEG-aldehydes (Hemenway et al., 2012). The puried product nolonger exhibits oxidative activity but the carbonyl compounds arenot eliminated (Ashani and Catravas, 1980). Another treatment toprevent hydroperoxide formation is the removal of dissolvedoxygen in the PEG by applying a vacuum (Kumar and Kalonia,2006).

Peroxides and aldehydes can be eliminated by sodiumthiosulfate of sodium borohydride (NaBH4) treatment (Ray andPuvathingal, 1985).

Formaldehyde can interact with API, excipient and gelatin shellscontaining NH group (Nassar et al., 2004).

120 V. Jannin et al. / International Journal of Pharmaceutics 466 (2014) 109121As glycerides, high molecular weight PEG and PEG esters cancrystallize in various polymorphs, mainly in zigzag or helicalconformation (Neyertz et al., 1994). The most stable polymorphcan be obtain either by controlling the crystallization rate of thepolyoxylglycerides or by treating the sample by a thermaltreatment after crystallization (Brubach et al., 2004; Jannin, 2009).

4. Conclusions

This review shows that the key excipient characteristicsimpacting drug product quality and functionality derive fromthe quality of raw materials used and the manufacturing processparameters 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 thehydroxyl value, and also to the presence of impurities or minorcomponents (free fatty acids, peroxides, aldehydes, soaps, alkalineimpurities and dioxane). The CPPs controlling the excipient qualityare the lipid/alcohol ratio in the reaction mixture, the quality of thenitrogen blanketing, parameters used for synthesis leading to theintended equilibrium of the composition (duration, temperature,catalyst), and nally the rening steps eventually implemented(deodorization, neutralization and ltration).

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Polyoxylglycerides and glycerides: Effects of manufacturing parameters on API stability, excipient functionality and processing1 Introduction2 Nature of lipids/excipients2.1 Glycerides - definition2.2 Natural sources of lipids2.3 Extraction and refinement of lipids2.4 Manufacture of lipid excipients - glycerides2.4.1 Interesterification2.4.2 Esterification, fat splitting, and transesterification

2.5 Critical excipient characteristics: benefits and interactions with other components in drug products

3 Polyoxylglycerides3.1 Nature of excipients3.2 Manufacturing processes3.2.1 Alcoholysis of triglycerides with PEG3.2.2 Direct esterification of fatty acids or methyl esters alcoholysis3.2.3 Ethoxylation of fatty acids

3.3 Critical excipient characteristics: benefits and interactions with other components in drug products

4 ConclusionsReferences