Reaching Further Together

WHITE PAPER

PRODUCING THE PERFECT SOFT GEL

This white paper outlines the key considerations to ensure gelatin is enhanced for soft gel formulation, efficient gel production and optimal API delivery as well as the potential challenges that Contract Development and Manufacturing Organizations (CDMO) could face if the right gelatin is not selected. It also discusses research that Rousselot has conducted, highlighting the impact of factors including ingredient compatibility, molecular weight and gelatin bloom on the quality and stability of soft gel capsules.

By Pierre-Albert Thomas, Global Technical Support Manager Rousselot, Dec. 2016

1 MarquesMRC,ColeE,KruepD,GrayV,MurachanianD,BrownWEandGiancasproGI.Liquid-filledGelatinCapsules.PharmacopeialForum2009Vol.35(4)

Due to its unique functional capabilities and full compliance with the human body, gelatin is the main ingredient in soft gelatin capsules, commonly known as soft gels. Soft gel manufacturers constantly work on new formulations to accommodate specific fills, develop new types of soft gels such as delayed release or chewable capsules, or to reduce costs. However, creating a soft gel delivery system that fulfills the latest specifications and end-use requirements is a complex and highly challenging process.

Choosing a high quality gelatin with the right characteristics is fundamental to achieving optimum soft gel capsules and this often requires a specific gelatin type. For instance, the soft gel capsule must allow optimal delivery oftheactivepharmaceuticalingredient(API)tothebody. Therefore,softgelstabilityandcrosslinkingpropertiesofthegelatinusedinmanufactureshouldbeunderstoodandtakeninto consideration. Moreover, using the right gelatin is also central to promoting an efficient and smooth manufacturing process so as to avoid typical soft gel defects such as twin, leakages,oddsandbrittleness.Criticalstepsincludepreparation of a gel mass that displays consistent quality and

minimal foaming, film manufacture and drying,therefore,gelatinmustbesoluble,easytouseandexhibitgoodmechanicalstrength.

GELATIN, A KEY EXCIPIENT FOR SOFT GELS Gelatinisafullydigestible,naturalproteinextractedfromcollagenfoundintheskin,bonesandconnectivetissuesofanimals.

CollagenFibrils CollagenMolecules(triplehelix)

α-chains

Aminoacidchains

CollagenFibers

Figure1:Thestructureofcollagenfibres.

Itsavailability,versatilityanduniquefunctionalcapabilitiesincludingfilmforming,thermo-reversibilityandrapidabsorptioncontributetoitsextensiveuseinanumberofpharmaceutical applications.1 These include soft gel capsules whose popularity among consumers is driving the research into the development of new formulations.

INTRODUCING PIERRE-ALBERT THOMAS Pierre-Albert Thomas is the Global Technical Support Manager at Rousselot, he and his team are responsible for bringing technical solutions to all pharma, food and nutrition accounts worldwide. Pierre-Albert joined Rousselot in 2003 as the Technical Account Manager for Japan.

From 2006 to 2011 he was responsible for the Technical Support and the Application Laboratory of the Asian Pacific region. With a degree in Food Science from the AgroParisTech University, Pierre-Albert has 20 years’ experience in the food industry and an extensive knowledge of gelatin and its use in pharmaceutical and food applications.

INTRODUCTION

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Figure2:Thefunctionalcapabilitiesandpropertiesofadesiredgelatin excipient for soft gel capsules.

Producing soft gels with consistent quality and integrity remains a high priority for the pharmaceutical industry. However, this is often difficult due to the dynamic nature of soft gel products and the sophisticated technology required in their manufacturingprocess.Akeyandvitalingredientinsoftgelsisgelatin. Choosing the right type of gelatin with the appropriate functional properties plays a critical role in an efficient and smooth manufacturing process which will yield an optimally performing capsule without any defects.

GELATIN FOR OPTIMAL FORMULATION CDMOsareincreasinglylookingtodevelopnewsoftgelformulations.Theobjectivesforthismaybetoaccommodatespecific fills, to develop new types of soft gels such as delayed releaseorchewablecapsulesortoreducecosts.Moreover,theincreasingnumberofAPIsbeingdeveloped means that manufacturers need to takeintoconsiderationtheinteractionsthatmayoccurbetweentheshellandthefillwhendeveloping new formulations. Choosing a high quality gelatin with specific characteristics thatwillfulfilltheobjectiveoftheend-productis crucial. However, to meet the specific needs of the product’s therapeutic action as well as consumer preferences, an appropriate gelatin with the right properties andfunctionalitiesoftenneedstobeconstructed.

Tests on lecithin soft gel formulations prove that factors including gelatin type and processing conditions can have a significantimpactontheleakageriskofthesoftgelshell. For example, without using a high wedge temperature during manufacture, gelatin types with greater molecular weight form seals less readily due to their high viscosity, causing soft gel mis-shapeandleakage.Testsalsoconcludedthat,intheconditionsoftheexperiment,alkalineormixed-processgelatinsoftgelcapsulesshowedlessleakagethangelatinsmanufacturedthrough acid processes; and optimizing the type of gelatin and encapsulation wedge used during soft gel manufacture decreasedtherateofleakagefrom2%toalmost0%(InternalRousselotstudy,WenzhouApplicationLab,April2016).

Figure3demonstratesthesignificanceofoptimizingencapsulationwedgeduringmanufactureforbettersealinginsoft gel capsules, showing that an optimal range of gel mass viscosityhasbeendeterminedasafunctionofthetypeofencapsulation wedge.

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4,000 20,000

30,00015,00010,000

Optimized wedge Regular wedge

Gelmass viscosity, mPa.s

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Optimized wedge Regular wedge

Gelmass viscosity, mPa.s

4,000

10,000 15,000

20,000

30,000

Gel mass viscosity, mPa.s

Optimized wedge Regular wedge

Figure3:Therelationbetweenencapsulationwedgeandgelmassviscosity(InternalRousselotstudy,WenzhouApplicationLab,April2016).

TRANSPARENCY

NATURAL PROTEIN

MELTING AT BODY

TEMPERATURE

EMUL

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FILM FORMING

FOAMING

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THERMO-REVERSIBILITY

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Wedge

The aim for CDMOs is defect-free production of optimal soft gel capsules. However, the manu-facturing process can prove challenging. The critical steps during this stage include gel mass preparation, ribbon formation and drying. The gelatin used must be soluble, easy to use and have good mechanical strength.

A quality gel massPreparing a gel mass that displays consistent formulation performance and minimal foaming is critical to prevent increased production costs and end product defects. Due to its amphiphilicnature,havingbothhydrophobicandhydrophilicproperties,gelatinexhibitsfoamingcharacteristicsbydecreasinginterfacialtension.Agoodunderstandingoffoamcapabilityandstabilityofthedifferenttypesofgelatinisessential to have full control of the soft gel manufacturing process, where foaming can cost additional vacuum time to the manufacturing process and impact productivity.

In this context, Rousselot has developed a comparativeanalysis test to allow soft gelatin manufacturers to evaluate the intrinsic foaming characteristics of different gelatin types.If foaming gelatin is used, stirring conditions and the vacuum havetobeadaptedtolimitthefoamingelmass.

EFFICIENT SOFT GEL PRODUCTION

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160

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050 100 150 200 250 300

Time(s)

Foam

vol

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Graph1:Comparativeanalysisoffoamcapacityandfoamstabilityofdifferentgelatintypes.(InternalRousselotstudy,GhentR&DLab,January2016).

Graph1showsthreecurvesthatrepresentthreedifferentgelatin types – Type1 with high foam function and high stability,Type2withahighfoamfunctionbutlowstability,and Type3,lessfoamfunctionandstability.

Everycurveshowstwophases–Phase1showingtheincreaseoffoamvaluefollowingtheinjectionofaninertgasandPhase2,thevaluedecreaseaftertheinjectionofgas.

Asfoamingisundesirableinsoftgelformulations,Rousselot’scomparativetestisvaluablefortheselectionofgelatin and operating conditions.

Gel mass

2 Liquid-filledGelatinCapsules.PharmacopeialForum2009Vol.35(4)

The perfect ribbonGelatin’s unique film-forming functionalities allow it to set quicklyandformreproduciblefilmsofdefinedthicknessknownasribbons.Thisstagerequiresextremeprecision,withmanufacturers having to accurately monitor and control gelatintemperature,ribbonthickness,seamwidthandfillquantity. The gelatin’s film-forming and viscosity properties are crucial to the success of this producing step. For instance, gelatin’s processing procedures have a strong impact on its viscosityandthereforeitsfilm-formingcapabilities. Thereisastrongrelationbetweenviscosityandfilmforming: viscosity represents the molecular weight of the gelatin and thereforeinfluencesthekineticsoftheformationofthegelatinnetwork.Thishasanimpactnotonlyonthespeedatwhichthegelatinribbonwillsetbutalsoonitsqualityanditinfluencesthe temperature at which the gelatin will melt and reset during encapsulation.Findingtherightvisco-elasticbehaviorofthegelatinsystemisthereforeessentialtocreatetheperfectribbonfor soft gel capsules as well as to ensure production efficiency.

Drying to preserve shelf-lifeIn order for soft gels to remain in perfect conditions during their shelf-life, they must undergo a drying process to prevent stickiness.ARousselotstudyperformedonfishoilformulations highlights the effect of final moisture level in soft gelcapsules,showingthatamoisturelevelabove11%significantlyincreasestheriskofstickiness(Graph2).Rousselot research also found that the parameters of the dryingstage,suchasdryingconditionsandkinetics,arekeytoachievingasuitablemoisturelevel.Inaddition,softgelsprepared with different plasticizers, such as PEG, require different drying regimes than soft gels prepared using glycerol orsorbitol.

Moisture > 11% Moisture < 11%Normal15%

Sticky85%

Normal94%

Sticky6%

Graph2:Theeffectoffinalmoisturelevelonsoftgel(InternalRousselotStudy,WenzhouApplicationLab,Sept.2013)

Graph3highlightstheinfluenceofdifferenttemperatureandrelativehumidity(RH)combinationsonthefinalmoisturecontent.Thegraphshowsthatalthough25°Cdegreesat25%relative humidity permits more water evaporation in the first twodaysofdrying,itis15°Cdegreesat15%relativehumidityconditions which are the most effective conditions to reach the optimal lower moisture content of capsules which will prevent stickinessduringtheshelflife2.

Graph3:Theeffectsofdifferenttemperature/RHcombinationsonthefinalmoisturelevelofgelatin.(InternalRousselotstudy,Wenzhouapplicationlab,Oct.2012)

Optimized process speed Choosingagelatinwithhighsolubility,usabilityandlowviscosityabove50°Cisimportantforoptimizingthespeedofproduction. Gelling proximity, setting temperature as well as thethermoreversibilitycharacteristicsoftheselectedgelatinallinfluencehighspeedencapsulation.Aswellasthis,gelatinmust have optimal mechanical strength and elasticity properties to allow stretching during filling.

Drying days

22

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0 1 2 3 4 5 6 7

T(°C)/RH(%)15°C/15%

T(°C)/RH(%)25°C/25%

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s IngredientsGelatinWaterGlycerin

Recipe41.7%41.7%16.6%

The influence of different drying conditions

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Ultimately, the reason for developing a soft gel capsule is so that it can effectively deliver an API. The bioavailability of actives in a soft gel depends on the dissolution of both its shell and fill as well as the gastro-resistance of the API. The capsule must also protect APIs during storage, only releasing them at the correct time and location in the body once consumed. However, soft gels can be sensitive to heat and moisture during storage, affecting the shelf-life stability3. To prevent instability for optimal API delivery, solute migration and crosslink minimization can be avoided by choosing a compatible gelatin with the right characteristics; and gastro-resistance can be managed with the addition of a biopolymer coating.

Shell inertnessAmajorchallengeinthedevelopmentofsoftgelsisthattheyare very dynamic systems. The physical migration of componentsbetweenshellandfillaswellasfromtheexternalenvironment to the shell, and the occurrence of physical and chemicalreactionsbetweentheshellandfillcomponentscancauseinstability,brittlenessandshellsoftnessorevenlossofshapeaffectingtheprotectionoftheAPIagainstoxidationandcausingpossiblerecrystallization.

LOWMOISTURE

FILL

Shell -35%

Figure4:WatermigrationinaPEG-filledcapsuleimmediatelyfollowingencapsulation.

PEG-basedsystems,forexample,exhibitagradientinthemoisturelevelsbetweenthehydrophilicPEGfillandtheshell. This causes migration of water following encapsulation and subsequentinstability,reducingtheeffectivenessofthecapsule.However,thiscanbeavoidedwithcarefulchoiceofgelatinprocessing techniques and shell formulation.

CrosslinkingExtensivecrosslinkingi.e.theformationofstrongchemicallinkagesbetweengelatinchains,cancausetheshelltobecometough,rubberyandinsolubleaffectingsoftgelstability.Research has revealed that some parameters, including gelatin molecularweightdistribution,mayimpacttheabilityofgelatintocrosslink;howevercustomizedgelatinscanpreventcrosslinkingandsubsequentinstability(graph4).Rousselothasdevelopedaprotocolpredictingthebehaviorofgelatininthepresenceofcrosslinkerstohelpthepharmaceuticalindustryconstruct the optimal gelatin type for their soft gel product.

High reactivity

Vis

cosi

ty

Low reactivityCrosslink reactivity

Graph4:Theeffectofdifferentgelatintypesoncrosslinkingbehaviorinthepresenceofaldehydes.Asteepincreaseinviscositycorrespondstoincreasedcrosslinking.(InternalRousselotstudy,GhentApplicationlab,Oct.2016)

3 ShankerGandTabibiE.WaterinsolubleDrugFormulation,2ndEdition,CRCPress2008

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OPTIMAL API DELIVERY

The manufacture of high quality gelatin-based soft gels that fulfills the end-use requirements and meets consumer demands as well as stringent industry regulations, is a complex challenge for pharmaceutical manufacturers. A deep understanding of the soft gel market and the capsule production process is key to choosing the correct gelatin for optimal formulation, an efficient production process and effective API delivery. Rousselot can provide the support needed to succeed.

THE WORLD LEADING PRODUCER OF NATURAL GELATIN AND COLLAGEN PEPTIDESRousselot, the world leading producer of natural gelatin and collagen peptides, offers CDMOs in the pharmaceutical industry an extensive range of world class gelatin products and solutions as well as expertise and innovation in soft gel manufacture. Partnering with the Rousselot team means benefitingfromanimpressiveheritageof125years’worldwideexperience in the production and application of pharmaceutical gelatin. Customers have access to a comprehensive service and exceptionalunderstandingofthesoftgelmarkethelpingtoeliminateriskduringmanufacture,maximizingproductivityatall stages of the process and saving costs.

Rousselot’ssafe,non-allergenicandfullycompatiblegelatinsareobtainedbycarefulselectionofrawmaterialsandproduced in full compliance with the highest quality, safety standardsandpracticesincludingIFS,HACCPandGMP.Awidevariety of certified Halal and Kosher gelatins is also proposed to Rousselot’s customers.

Rousselotguaranteesconsistentquality,safetyandtraceabilityto ensure the perfect gelatin is created for optimal soft gel success.Rousselotalsoproactivelytakesstepstoachieve

greaterprogressinitsenvironmentalandethicalbusinessgoals,implementingsustainableproductionmethodstoreduceenergy use and water consumption for the protection of the planet.

TECHNICAL

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Figure5:Rousselotpromises: Expertisesupportedlocally,higheststandardsandfullresponsibility.

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CONCLUSION

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About Rousselot. Reaching Further Together.RousselotisabrandofDarlingIngredientsInc.Rousselotisthegloballeader*ofgelatinandcollagenpeptides. Rousselot’swiderangeofcollagenpeptidesaremarketedunderthePeptanbrand.Weworkinpartnershipwithourcustomersallovertheworld,delivering innovative and advanced ingredient solutions manufactured through state of the art operations. We help our customers achieve their goals,enablingthemtocreateworldclasspharmaceutical,foodandnutritional products to inspire and excite today’s demanding consumers.

*Source: Global Industry Analysts, Inc, Gelatin a Global Strategic Business report, Nov 2016

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