Syringe SiliconizationTrends, methods, analysis procedures

Bruno Reuter, Claudia Petersen . Gerresheimer Bünde GmbH, Bünde

Correspondence: Claudia Petersen, Gerresheimer Bünde GmbH, 32257 Bünde, Erich-Martens-Str. 26-32;e-mail: c.petersen@gerresheimer.com

Summary

Ready-to-fill, i.e. sterile, prefillable glass syringes, are washed, siliconized, sterilizedand packaged by the primary packaging manufacturer. They can then be filled by thepharmaceutical companies without any further processing. These days the majority ofprefillable syringes are made of glass and the trend looks set to continue. The silicon-ization of the syringe barrel is an extremely important aspect of the production ofsterile, prefillable glass syringes because the functional interaction of the glass barrelsiliconization and the plunger stopper siliconization is crucial to the efficiency of theentire system. Both inadequate and excessive siliconization can cause problems in thisconnection. The use of modern technology can achieve an extremely uniform distri-bution of silicone oil in glass syringes with reduced quantities of silicone oil. Anotheroption for minimizing the amount of free silicone oil in a syringe is the thermal fixationof the silicone oil on the glass surface in a process called baked-on siliconization.Plastic-based silicone oil-free or low-silicone oil prefillable syringe systems are a rel-atively new development. Silicone oil-free lubricant coatings for syringes are also cur-rently in the development phase.

Introduction

Primary packaging for injectables al-most exclusively comprises a glasscontainer (cartridge, syringe, vial)and an elastomer closure. Ampoulesare an exception.

Elastomers are by nature slightlysticky, so all elastomer closures(plunger stoppers for syringes andcartridges, serum or lyophilizationstoppers) are siliconized. Silicon-ization prevents the rubber closuresfrom sticking together and simplifiesprocessing of the articles on the fill-ing lines. For example, it minimizesmechanical forces when the stoppersare inserted. Siliconization is there-fore essential to process capability.

Although syringes and cartridgesare always siliconized, this appliesto a lesser extent to vials and am-poules. On the container the silicon-ization provides a barrier coating be-tween the glass and drug formu-lation. It also prevents the adsorptionof formulation components on theglass surface. The hydrophobic deac-tivation of the surface also improvesthe containers’ drainability. In prefil-lable syringes and cartridges, silicon-ization also performs another func-tion. It lubricates the syringe barrelor cartridge body enabling theplunger to glide through it. Silicon-ization of the plunger stopper alonewould not provide adequate lubrica-tion.

Silicone oils are ideal as lubricantsbecause they are largely inert, hydro-phobic and viscoelastic. Chemicaland physical requirements for lubri-cants are set out in the relevantmonographs of the American (UnitedStates Pharmacopoeia, USP) and Eu-ropean (Pharmacopoeia Europaea,Ph. Eur.) pharmacopoeias [1, 2]. Sec-tion 3.1.8 of Ph. Eur. also defines akinematic viscosity of between 1,000and 30,000 mm2/s for silicone oilsused as lubricants [3]. By contrast,the monograph for polydimethylsi-loxane (PDMS) in the USP [2] per-mits the use of silicone oils with aviscosity of 20 to 30,000 centistokes.However, increasingly stringent qual-ity requirements and new bioengi-

ZurVerw

endungmitfreundlicher

Genehm

igungdes

Verlages

/For

usewith

permission

ofthe

publisher

Focus PackagingEnglish reprint of the German original publication

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany) 1Reuter and Petersen . Siliconization

neered drugs are now taking silicon-ization technology to its limits. Non-homogenous siliconization whichcan occur when simple coating tech-niques are used on longer syringebarrels can, in some cases, lead tomechanical problems. These includethe incomplete drainage of the sy-ringe in an auto-injector or high glid-ing forces. Silicone oil droplets arealways observed in filled syringes.The number of silicone oil dropletsincreases in line with the quantity ofsilicone oil used. Droplets which arevisible to the naked eye could beviewed as a cosmetic defect. At sub-visual level, the issue of whether sili-cone oil particles could induce pro-tein aggregation is currently underdiscussion [4].

In light of this development, thereis an obvious trend towards opti-mized or alternative coating tech-niques. Attempts are being made toachieve the most uniform possiblecoating with a reduced quantity ofsilicone oil and to minimize theamount of free silicone oil by wayof baked-on siliconization. In thiscontext, reliable analysis technol-ogies that can be used to make qual-itative and quantitative checks onthe coating are absolutely essential.Alternative coating techniques arealso being developed.

Silicone oils and theirproperties

Silicone oils have been used for half acentury in numerous pharmaceuticalapplications. For example, they areused as lubricants in pharmaceuticsproduction and as inert pharmaceu-tical base materials (e.g. soft capsulewalls) [5]. Trimethylsiloxy end-blocked polydimethylsiloxane (PDMS,dimethicone) in various viscosities

is generally used for siliconization(Fig. 1).

The most frequently used siliconeoil for the siliconization of primarypackaging components is DOWCORNING® 360 Medical Fluid, whichhas a viscosity of 1,000 cSt. PDMS isproduced by reducing quartz sand tosilicone metal. In the next step, thesilicone reacts directly with methylchloride in a process called Müller-Rochow synthesis to create methylchlorosilanes. In this process, a mix-ture of different silanes is produced,the majority of which (75%–90%) aredimethyldichlorosilane (CH3)2 SiCl2.After distillative separation, the di-methyldichlorosilane is convertedby hydrolysis or methanolysis intosilanols which condense into low-molecular-weight chains and cycles.In an acidic (cationic) or alkaline (an-ionic) catalyzed polymerization,polydimethylsiloxanes with hydroxyfunctions are generated. After the ad-dition of trimethylchlorosilane theyare furnished with trimethylsiloxyend groups. The short chain mole-cules are removed from the resultingpolydisperse polymers by way of va-porization, leaving deployable PDMS.

The characteristic aspect of thePDMS molecule is the Si-O bond.With a bond energy of108 kcal/mol,it is considerably more stable thanthe C-O bond (83 kcal/mol) or theC-C bond (85 kcal/mol). PDMS is ac-cordingly less sensitive to thermalloads, UV radiation or oxidationagents. Reactions such as oxidation,polymerization or depolymerizationdo not occur until temperatures ex-ceeding 130 °C. The molecule alsotypically has a flat bond angle (Si-O-Si 130 °C) which has low rotationenergy and is especially flexible(Fig. 2). A high bond length(1.63ÅSi-O as compared to 1.43Å for C-O)makes the molecule comparativelygas-permeable [6].

The spiral shaped (and thereforeeasily compressible) molecule is sur-rounded by CH3 groups which areresponsible for the chemical and me-chanical properties of PDMS. Themolecule’s methyl groups only inter-

act to a very limited extent. This en-sures low viscosity, even with highmolecular weights, which simplifiesthe distribution of PDMS on surfacesand makes it a very effective lubri-cant. PDMS is also largely inert andreactions with glass, metals, plasticsor human tissues are minimal. TheCH3 groups make PDMS extremelyhydrophobic. It is insoluble in water,but soluble in non-polar solvents [6].

Siliconized syringes

As already explained the syringe sys-tem only works if the glass barrel andplunger stopper siliconization arehomogenous and optimally harmo-nized. For needle syringes, silicon-ization of the needle is also essentialto prevent it sticking to the skin,thereby minimizing injection pain.For the so-called oily siliconizationof the syringe glass barrel DOW COR-NING® 360 with a viscosity of1,000 cSt is used. The DOW COR-NING® 365 siliconization emulsionis often used in the baked-on silicon-ization process. The needle is silicon-ized using a wipe technique duringready-to-fill processing. DOW COR-NING® 360 with a viscosity of12,500 cSt is used. Another option isthe thermal fixation of silicon oil onthe needle during the needle mount-ing process.

The goal of syringe barrel silicon-ization is to obtain the most evenanti-friction coating possible alongthe entire length of the syringe inorder to minimize break loose andgliding forces when the plungerstopper is deployed (Fig. 3).

ZurVerwendung

mitfreundlicher

Genehmigung

desVerlages/Forusewithperm

ission

ofthepublisher

Focus PackagingEnglish reprint of the German original publication

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany)2 Reuter and Petersen . Siliconization

Fig. 1: Polydimethylsiloxane.

Fig. 2: 3D-structure of polydimethylsiloxane.

Inadequate siliconization of thesyringe barrel, particularly the exist-ence of unsiliconized areas, cancause slip-stick effects that impairthe syringe’s function. The forces inthe injection process can then be toohigh or the entire system can fail.Since inadequate siliconization andgaps in the coating are often foundon the lower end of the syringe (luertip/needle end), it is possible that thesyringe will not be completely emp-tied. Such defects can remain undis-covered, particularly in auto-injec-tors since these are closed systems.The result could be that an inade-quate dosage of the medication isadministered.

The obvious solution is to increasethe amount of silicone oil used toachieve a homogenous coating. How-ever, as already mentioned, increas-ing the amount of silicone oil used isalso associated with higher quan-tities of silicone particles in the solu-tion. With protein-based drugs, inparticular, undesirable interactionswith silicone oil particles cannot beruled out. Sub-visual silicone oil par-ticles are thought to promote proteinaggregation which can increase theseverity of immune responses andreduce the drug’s tolerability. How-ever, the underlying mechanism isnot yet fully understood. There is adiscussion as to whether protein ag-gregation is influenced by additionalmotion, e.g. shaking the syringe [7].Experiments have also shown thatwhen silicone oil in excess of 1 mg/syringe is used the additional siliconeoil does not further reduce glidingforces.

The interior siliconization of glasssyringe barrels has another advan-

tage. It prevents the drug solutionfrom interacting with the glass sur-face and rules out related problemssuch as the loss of active ingredientsthrough adsorption or pH valuechanges due to alkali leaching. Prefil-lable glass syringes are only manu-factured from high quality type 1 bo-rosilicate glass. However, sodiumions can still leach out of the glasssurface if the syringe contains anaqueous solution and is stored for along period of time. This leads tohigher pH values which could beproblematic in unbuffered systems.Acidic environments foster this proc-ess.

Si-O-Na + H20 ↔ SiOH + NaOH

In alkaline environments, on theother hand, an etching process is ob-served.

2NaOH + (SiO2)X → Na2SiO3 + H2O

Aqueous solutions with a high pHvalue cannot therefore be stored forlong periods of time in borosilicateglass containers. They have to be lyo-philized and reconstituted beforeuse. In extreme cases, the etching ofthe glass surface can cause delami-nation. Hydrophobic deactivation ofthe container by siliconization effec-tively protects the glass surface.

Optimized siliconization

For the above-mentioned reasons,the main objective in siliconizationis to achieve the most homogenouspossible coating with the minimumpossible quantity of silicone oil. Ini-tially it is necessary to establish theminimum quantity of silicone oilwhich will reliably satisfy the qualityrequirements of the application. Inthe production of ready-to-fill sy-ringes, siliconization generally takesplace after washing and drying. Fixednozzles positioned at finger flangelevel under the syringe barrel spraythe silicone oil onto the inside sur-face. In long syringes, the silicone oilis sometimes unevenly distributedand the concentration of the siliconeoil is lower at one end of the syringe(luer tip/needle end). The use of div-ing nozzles can considerably im-prove the evenness of the coatingacross the entire length of the syringebody. In this process, the nozzles areinserted into the syringe to apply thesilicone oil ( finely atomized) in mo-tion. The result is practically linear asis shown by the closely bundled glid-ing forces in the force path diagram(Fig. 4).

Studies on 1 ml long syringes haverevealed considerable potential forreducing the amount of silicone oilrequired. In the experiment, the

ZurVerw

endungmitfreundlicher

Genehm

igungdes

Verlages

/For

usewith

permission

ofthe

publisher

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany) 3Reuter and Petersen . Siliconization

Gliding force

Fig. 3: Extrusion force profile of a prefillablesyringe.

Fixed Nozzle

Diving Nozzle

– Fav break loose force

= 2.1 N

– Faw gliding force

= 2.4 N

– Fav break loose force

= 1.7 N

– Faw gliding force

= 0.5 N

m = 0.8 mg, v = 300 mm/min, empty 1 ml long LC Syringes

Fig. 4: Comparison of extrusion force profiles diving nozzle vs. fixed nozzle.

quantity of silicone oil per syringecould be reduced by 40 % withoutany impairment of the system’s func-tional properties (Fig. 5). In practicethe calculation of the optimumquantity of silicone oil has to takesyringe volume, plunger stopper type(coated/ uncoated), plunger stopperplacement method (seating tube/vacuum) and application require-ments (injection systems) into ac-count. Plunger stoppers from differ-ent suppliers not only differ in termsof the type of rubber used and theirdesign, they are also coated with sili-cone oils of different viscosities. Thesiliconization methods also differconsiderably. These variables canhave a bigger impact on the syringesystem’s functional properties thanthe syringe siliconization of differentsuppliers, as shown by Eu et al. [8].

Baked-on siliconization

Another key advancement in silicon-ization technology is the baked-onsiliconization technology. It involvesthe application of silicone oil as anemulsion which is then baked on tothe glass surface in a special kiln at aspecific temperature and for a spe-cific length of time.

In the baked-on process, both hy-drogen and covalent bonds form be-tween the glass surface and the poly-dimethylsiloxane chains. The bondsare so strong that part of the siliconeoil cannot be removed with solventand a permanent hydrophobic layeris created (Fig. 6). In addition theaverage molecule weight increasesas a result of polymerization andthe vaporization of short chainpolymers. The resulting, extremelythin layer of silicone in conjunctionwith the low quantity of silicone oilused in the emulsion minimizes freesilicone in the syringe and ensuresthat the required quality of finish isachieved. The layer thickness meas-ures 15–50 nm. By comparison, theaverage layer thickness with oily sili-conization is 500–1,000 nm.

Baked-on siliconization reducesthe measurable quantity of free sili-

cone oil to approx. 10 % of the nor-mal value. As a result, there are fewersub-visual and visual silicone oil par-ticles in the solution. This silicon-ization process is therefore rec-ommended for use with sensitiveprotein formulations. It is also ad-vantageous for ophthalmologicalpreparations which are associated

with very stringent re-quirements as regardsparticle contamination.

Another benefit isthe stability of the me-chanical properties ofthe filled syringethroughout its shelf life.The ribs of a plungerstopper press into thesilicone layer when asyringe with oily sili-conization is stored for

long periods of time and the glasscomes into direct contact with therubber. Since elastomers are alwaysslightly sticky, the break loose forcesincrease over the storage period.With baked-on siliconization, how-ever, this phenomenon is not ob-served to the same extent (Fig. 7).The break loose force remains prac-

ZurVerwendung

mitfreundlicher

Genehmigung

desVerlages/Forusewithperm

ission

ofthepublisher

Focus PackagingEnglish reprint of the German original publication

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany)4 Reuter and Petersen . Siliconization

Fig. 6: Baked-on siliconization.

Standard 1ml long syringe*Fixed Nozzlem = 0,8 mgV = 100 mm/minBF

mean = 2.5 N

EFmean

= 1.7 N

Standard 1ml long syringe*Diving Nozzlem = 0,5 mgV = 100 mm/minBF

mean = 1.7 N

EFmean

= 0.5 N

* Empty syringes

Optimized siliconization

Fig. 5: Extrusion force profile after optimized siliconization.

The baked-on siliconization providesa permanent coatingÆ Breakloose forces increase overstorage time is smaller

Oily siliconized syringe Baked-on siliconized syringe

Direct rubber/glass contact leads to higherbreak loose forces over the storage period

Storage Storage

Fig. 7: Comparison of syringes with oily and baked-on siliconization.

tically constant over the entire stor-age period.

Analysis methods

The optimization of the silicon-ization process necessitates reliablequalitative and quantitative analysismethods. Online methods for theone-hundred percent control of sili-

conization during production are notcurrently available. In process con-trol, random samples are taken andseveral destructive and non-destruc-tive methods are used.

In the glass dust test, the silicon-ization is made visible by dusting itwith finest glass particles (Fig. 8).This destructive method is simplebut time-consuming. It is also asso-ciated with the problems that thequality of the siliconization is subjec-tively evaluated and the results areaffected by temperature and air hu-midity.

Measuring the gliding force is anindirect method of determining the

evenness of the siliconization(Fig. 9). This process is also destruc-tive and associated with problems.For example, the results are in-fluenced by the positioning of theplunger stopper and there is nostandard for extrusion speed. Avalue of 100 mm/min is often takenfor empty syringe systems; and up to380 mm/min. for filled systems.

Relatively fast quantitative andnon-destructive results can be ob-tained with reflexometry. For exam-ple, the Layer Explorer UT (Fig. 10)which is manufactured by rapID scansthe syringe body line-by-line. It canmeasure layer thicknesses of 15 nmto several thousand nm with a preci-sion of 5 nm (Fig. 10.1). Scanning a40 mm syringe with the Layer Ex-plorer takes approximately 1 minute.

Another non-destructive tech-nique such as the one developed byZebra Science (Fig. 11) is based ondigital image processing. The entireinside surface of the syringe barrel isimaged to visualize typical silicon-ization surface structures. The tech-nology captures these visual cues as adirect indication of silicone oil pres-ence and poorly siliconized areas(Fig. 11.1). It delivers fast qualitativeresults and is suitable for empty andfilled syringes. However, empty sy-ringes should be measured immedi-ately after siliconization becauseeven just half an hour after silicon-ization the distribution of the sili-cone provides a completely differentpicture and it takes a very expe-

ZurVerw

endungmitfreundlicher

Genehm

igungdes

Verlages

/For

usewith

permission

ofthe

publisher

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany) 5Reuter and Petersen . Siliconization

Fig. 8: Glass dust test: left – syringe siliconizedwith an diving nozzle, right – syringe siliconizedwith a fixed nozzle.

Fig. 9: Gliding force measurement.

Layer thickness in nm

Fig. 10: Silicone layer thickness measurement with the Layer ExplorerRapID (own data).

Fig. 10.1: Silicone layer thickness measurement with the Layer Explorer(own data).

rienced person to interpret the re-sults properly.

Unfortunately, this method is alsonot fast enough to facilitate 100 %online control during the washingand siliconization process.

Outlook

There is a trend towards reduced-sil-icone systems or baked-on silicon-ization in glass syringe finishing. Im-proved analysis techniques and abetter understanding of the phenom-ena involved support optimized useof silicone oil.

New issuesare arising as aresult of the useof innovativematerials orcoatings. Inlight of the in-creasing com-plexity of de-vices and themore wide-spread inci-dence of bi-opharmaceuti-cals with spe-

cific requirements, new alternativematerials for primary packagingproducts are becoming increasinglyinteresting. For example, the insidesurfaces of vials and syringes can becoated with pure SiO2 in a plasmaprocess to minimize their interactionwith drugs. Plastic systems based oncyclic olefins (COP/COC) are alsogaining in significance for prefilledsyringes and vials. COP syringes suchas the ClearJect TasPack by TaiseiKako Co. Ltd have glass-like trans-parency. Additionally, they have ahigher break resistance, their pH sta-bility range is larger and there is nometal ion leaching. Excellent dosageprecision is also very important inpackaging for bio-pharmaceuticals.In most cases siliconization is alsoessential in COP syringes. Siliconeoil-free systems are a brand new ap-

proach. The gliding properties of thefluoropolymer coating on speciallydeveloped plunger stoppers elimi-nate the need to siliconize plastic sy-ringes. There are as many innovativeideas for the development of primarypackaging products as there are in-novative drugs and syringe systems.

Literature

[1] United States Pharmacopoeia 35 NF 30.Dimethicone, The United States Phar-macopeial Convention Inc, Rockville,USA, 2011

[2] Pharmacopoea Europaea. 7. Ausgabe.Dimeticon, Deutscher Apotheker Verlag,Stuttgart, Deutschland, 2011, s. 2788

[3] Pharmacopoea Europaea. 7. Ausgabe.3.1.8 Siliconöl zur Verwendung als Gleit-mittel, Deutscher Apotheker Verlag,Stuttgart, Deutschland, 2011, s. 486

[4] Jones LS, Kaufmann A, Middaugh CR.Silicone Oil induced aggregation of pro-teins. J Pharm Sci 2005; 94(4):918-927

[5] Colas A, Siang J, Ulman K. Silicone inPharmaceutical Applications Part 2:Silicone Excipients. Dow Corning Corpo-ration, Midland, USA, 2001

[6] Colas A. Silicone in PharmaceuticalApplications. Dow Corning Corporation,Midland, USA, 2001

[7] Thirumangalathu R, Krishnan S, SpeedRicci M, Brems DN, Randolph TW, Car-penter JF. Silione Oil- and agitation-in-duced aggregation of a monoclonal anti-body in aqueous suspension. J Pharm Sci2009; 98(9):3167-3181

[8] Rathore N, Pranay P, Eu B. Variability insyringe components and its impact onfunctionality of delivery systems. PDAJ Pharm Sci and Tech 2011; 65:468-480

ZurVerwendung

mitfreundlicher

Genehmigung

desVerlages/Forusewithperm

ission

ofthepublisher

Focus PackagingEnglish reprint of the German original publication

TechnoPharm 2, No. 4, 238–244 (2012)© ECV . Editio Cantor Verlag, Aulendorf (Germany)6 Reuter and Petersen . Siliconization

Fig. 11.1: Visualization of syringe barrel sili-conization (Source: Zebra Science).

Fig. 11: ZebraScience visualization of siliconization.

Editor-in-chief: Claudius Arndt. Managing editor: Kerstin Jarosch. Publisher: ECV · Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH,Baendelstockweg 20, 88326 Aulendorf (Gemany). Phone: +49 (0) 8191-98578 12, Fax: +49 (0) 8191-98578 19. e-mail: redaktion-tp@ecv.de. http://www.ecv.de.Typesetting: Rombach Druck- und Verlagshaus GmbH & Co. KG (Germany) / Printed by Holzmann Druck GmbH & Co. KG, Bad Wörishofen (Germany). All rightsreserved.