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The use of silicones in pharmaceutical applications

Silicones are used in pharmaceutical applications as part of formulations, as well as

during manufacturing and in packaging. The term ‘silicones’ encompasses a large

number of compounds based on polydialkylsiloxanes. The most common are

trimethylsilyloxy-terminated polydimethylsiloxanes. Their applications include use as:

Silicones for pharmaceutical

applications – analytical

capabilities at Solvias

ACTIVE INGREDIENTSDimethicones and simethicones are used as active ingredients and antifoaming agents

in numerous anti-flatulent or anti-acid formulations. In pharmaceutical formulations,

while considered active ingredients, their effect is usually caused by their physical

properties, as polydimethylsiloxanes are not metabolized.1,2

The term ‘silicones ’ encompasses a large number of compounds based on polydialkylsiloxanes.

W H I T E PA P E R | J U N E 2 0 1 7

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EXCIPIENTS IN TOPICAL FORMULATIONS Silicones are known for their excellent biocompatibility and safety, their non-greasy and

non-staining properties and a pleasant, ‘silky’ touch. These properties make them ideal, and

thus widely used, as excipients in topical formulations and cosmetics. They can also affect

penetration rates of actives by improving film cohesion on the skin.

EXCIPIENTS IN CONTROLLED-RELEASE DEVICESSilicones are highly permeable to some active ingredients, especially those that are

lipophilic and of low-to-medium molecular weight. Therefore, drug release can be

controlled by diffusion through a silicone network.1,2

Silicones are widely used as active ingredients, antifoaming agents and excipients, and for siliconization, pharmaceutical

manufacturing operations and packaging materials.

SILICONIZED PARENTERAL PACKAGING COMPONENTSSilicone oils are used to lubricate the inner wall of glass containers to provide a barrier

between the glass and the drug formulation. The silicone layer causes a hydrophobic

deactivation of the surface, improving the containers’ drainability and preventing

adsorption of ingredients on the glass surface. Siliconization is particularly important for

prefillable syringes and cartridges. It lubricates the syringe or cartridge body, reducing

break loose and gliding forces, and allows for a tight connection between the cartridge and

the plunger stopper. The careful optimization of siliconization process parameters (including

baked on vs. sprayed on siliconization) can help to achieve a uniform coating while

minimizing free silicone oil.1,2,5

MANUFACTURING AND PACKAGING MATERIALSSilicone tubes, gaskets and elastomers are widely used in pharmaceutical manufacturing

operations or as packaging materials and, as such, are now receiving increased attention

in the assessment of extractables and leachables.

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Pharmacopeial testing of silicones for the use as excipients or actives

Silicones are produced and certified to meet the specifications of a variety of

pharmacopeia monographs. All manufacturers of drugs or substances used in

pharmaceutical manufacturing must ensure compliance with these quality standards and

Analytical testing of silicones in pharmaceutical applications

PRODUCT: APPLICATION

Dimethicone Anti-foaming, anti-flatulent agent Ph. Eur., USP-NF

Simethicone Anti-foaming, anti-flatulent agent Ph. Eur., USP-NF

Simethicone emulsion Anti-foaming, anti-flatulent agent USP-NF

Cyclomethicone Volatile carrier substance USP-NF

Silicone oil as lubricant Lubricant Ph. Eur.

Silicone elastomer for closures and tubings

Packaging, closures, tubing Ph. Eur.

Table 1: Relevant monographs in official pharmacopeial texts1, 2, 3, 4

Silicones are produced and certified to meet the specifications of a variety of pharmacopeia monographs. Manufacturers must

ensure compliance and test their products for conformity.

test their products for conformity to bring their products to market. Solvias offers a

broad portfolio of quality control and release-testing services to support our customers

to meet these requirements.

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Quantification of silicone levels in drug products can be required when silicones are part of the

formulation or for the control of silicone impurities. Inductively coupled plasma–optical

emission spectrometry (ICP-OES) is one technique for quantifying silicones. This atomic

spectrometry technique relies on inductively coupled argon plasmas to atomize and excite the

elements present in the sample solution, which emit light at characteristic wavelengths and

allow for quantitation via its intensity. While ICP-OES only discriminates between different

elements and not the silicone source (inorganic / organic etc.), it can determine the total

elemental Si content of a given sample and thus provide a worst-case scenario. Together with its

low limits of quantitation, this makes the technique very valuable for the control of silicone

impurities or for leachable studies. A second silicon determination after a solvent-extraction step,

or in combination with information available via other analytical techniques, can further enable

separate quantification of ‘organic’ Si (e.g. silicones) and inorganic Si (e.g. silicates).

Assay or impurity analysis in drug-product formulations and excipients

Quantitative Fourier transform infrared (FTIR) spectroscopy is another useful technique

for silicone quantification. Quantification of silicone content is performed via the strong

and specific Si-CH3 IR absorption band at about 1260 cm-1. While the achievable limit of

quantitation is not as low as with ICP-OES, the analysis is specific for silicones and thus it

can provide complementary information (for a summary of analytical methods suitable

for the analysis of silicones, see table 2).

ICP-OES can determine the total Si content of a given sample. Together with its low limits of quantitation,

this makes the technique very valuable for the control of silicone impurities and leachables.

ANALYTICAL TECHNIQUE

APPLICATION WORKING RANGE REQ. SAMPLE AMOUNT

Solvent Extraction and determination via FT-IR Spectrometry after pre-concentration step

Quantitation of extractable silicones in aqueous and drug formulations

From 0.01% or lower, depending on available sample volume

Depending on required LOQ

Monitoring of siliconization layer (sprayed on / baked on) in parenteral packaging devices (eg. Pre filled syringes)

50 µg/per device or lower up to several mg per device

Depending on method require- ments (from 1 device per determination)

Inductively coupled plasma-optical emission spectrometry (ICP-OES)

Determination of total elemental silicon in aqueous formulations

Approx. 0.1–100 mg/L 0.5 ml

Determination of organically bound elemental silicon in aqueous formulations

Approx. 0.1–100 mg/L 0.5 ml

Determination of total elemental Si in solid dosage forms

Approx. 0.1–100 % m/m 20–30 mg

Micro flow imaging Detection and Quantification of intrinsic silicon oil droplets and capability to distinguish them from other particulate matter

1 µm–100 µm Regarding imaging particles >5 µm can be distinguished

0.5 ml per run

Table 2: Techniques for silicone quantification and the control of silicone impurities at SolviasAnalyst determining silicone concentrations via FTIR spectroscopy

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SILICONIZATION CONTROLThe siliconization of syringes is an important aspect of the production of prefillable

syringes and other parenteral packaging components, and is pivotal to their

performance. Both inadequate and excessive siliconization can cause problems in this

regard.5 Due to increasingly stringent quality requirements, especially for new

biopharmaceutical formulations, siliconization control is critical. Effective monitoring of

the applied silicone quantities is thus crucial for prefilled syringe development and

quality control. A challenge for the development of suitable analytical methods is

presented by the hydrophobicity of silicone oil and the often relatively small quantities

applied. Extraction of the silicone with organic solvents followed by FTIR spectroscopy

can provide crucial quantitative information on the siliconization layers. The technique is

ideal for quality control of devices after the spray-on siliconization step and can even be

successfully applied to devices with baked-on silicone layers.6 Solvias has successfully

developed and implemented a range of methods for the reliable quantitation of silicones

applied during siliconization steps (spray-on and baked-on processing), see table 2.

Analysis of silicones in parenteral formulations and packaging components

Due to increasingly stringent quality requirements, especially for new biopharmaceutical

formulations, siliconization control is critical.

Silicone Air bubble Glass / Silica Protein aggregates

Different types of commonly encountered particulate contaminants in parenteral formulations. Images courtesy of Protein Simple

SILICONE OIL DROPLETS AS PARTICULATE CONTAMINATIONSilicone oil droplets are observed in pre filled syringes in devices siliconized by spray-on

and baked-on siliconization).5 The formation of silicone oil droplets in the sub-visible

particle size range is an important challenge. Formation of proteinaceous sub-visible

particles is a potential degradation pathway of biologics and has therefore gained

increased attention by health authorities. Sub-visible particulates in the size range of

0.1–10 microns have also shown strong immunogenicity potential. Thus, characterization

of the sub-visible particle population and discrimination between silicone oil droplets

and proteinaceous sub-visible particles becomes very important. Light obscuration is

the standard pharmacopoeial method to quantify sub-visible particles. However, the

method is not able to differentiate types of particles. Micro-flow imaging technology is

currently the only technique that provides the whole dataset of information required to

differentiate between those particle types. For this reason, the FDA suggests integration

of MFI technology into pharmacopeia methods (USP chapter <1787> Measurement of

sub-visible particulate matter / General information).3

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Rela

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Figure 1: Example: Comparison of leachables from silicone tube (red) and a silicone gasket (green)

Figure 2: Comparison of leachables from silicone tube (red) and a silicone gasket (green)

Semi-volatile silicones

Molecular weight: 150 -2000 Da

Solvias SOP: A.52.S837

Technique: PTV GC / MS

Semi / non-volatile silicones

Molecular weight: 150 -3000 Da

Solvias SOP: A.52.S855

Technique: Accurate Mass LC / MS / MS Orbitrap Q-Exactive FocusRe

lativ

e A

bund

ance

Silicone leachables may originate from tubes, gaskets and elastomers used in

pharmaceutical manufacturing operations or as packaging materials. Depending on

the molecular weight and analytical need, a variety of chromatography coupled mass

spectrometric techniques (GC-MS, LC-MS, see figures 1 and 2) can be utilized to screen for

leachables (see table 3). Further, worst-case scenarios can be established via determining

the total Si or silicone content with methods like ICP-OES, mentioned above.

Analysis of silicones as leachables from process equipment and packaging

ANALYTICAL TECHNIQUE

APPLICATION WORKING RANGE REQ. SAMPLE AMOUNT

GC-MS + GC-MS/MS (Headspace and Liquid Inj.)

Generic GC-MS/MS methods for the identification and semi-quantification of volatile to semivolatile extractables & leachables profiles in extracts of polymers or medical devices.

Mass range from 150 to 1200 Da, typically from 0.01mg/L – 100mg/L

Depending on required LOQ, approx. 1ml or 1 device

LC-MS + LC-MS/MS

Generic LC-MS/MS methods for the identification and semi-quantification of semivolatile to non-volatile extractables and leachables profiles in extracts of polymers or medical devices.

Mass Range from 600 to 3000 Da, typically from 0.01mg/L – 100mg/L

Depending on required LOQ, approx. 1ml or 1 device

Table 3: Techniques allowing structure identification and molecular weight determination at Solvias

Chromatography coupled mass spectrometric techniques such as GC-MS and LC-MS can be utilized to

screen for silicone leachables .

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The optimal choice or combination of silicone analysis methods can only be made after careful consideration of the analytical question to be answered. Our specialists’ long-standing expertise in modern imaging technology, spectroscopy as well as element and trace analysis means you can rely on Solvias to help you select and develop the analytical solution that best suits your needs.

The Solvias approach

References

1. Colas A, Siang J, Ulman K. Silicone in Pharmaceutical Applications Part 2: Silicone Excipients. Dow Corning Corporation, Midland, USA, 2001

2. Colas A. Silicone in Pharmaceutical Applications. Dow Corning Corporation, Midland, USA, 2001

3. United States Pharmacopoeia 40 NF 35. The United States Pharmacopeial Convention Inc, Rockville, USA, 2017

4. European Pharmacopoeia (Ph. Eur.) 9th Edition. 2017

5. Reuter B., Petersen C. Syringe Siliconization - Trends, methods, analysis procedures. TechnoPharm 2, No. 4, 238–244 (2012)

6. Funke S, Matilainen J, Nalenz H, Bechtold-Peters K, Mahler HC, Friess W. Analysis of thin baked-on silicone layers by FTIR and 3D-Laser Scanning Microscopy. Eur J Pharm Biopharm. 2015 Oct; 96:304-13. Epub 2015 Aug 24.

7. Jones LS, Kaufmann A, Middaugh CR. Silicone oil induced aggregation of proteins. J Pharm Sci 2005; 94(4):918-927

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