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Automatic stability analyses for pharmaceutics

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® o Pharmaceutical formulationssuspension (eye drops, drug powder, …)emulsion (cream, lotion, parenteral

emulsion, …)aerosol (pMDI, sprays, …)

o Stability is a critical issueparticle size (risk of embolism, …)sediment packing (drug dose, ease of

redispersion)creaming (drug dose, emulsion breaking)

Stability of pharmaceutics

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® Need for an accurate and objective technique to measure stability

Turbiscan® technology

Stability of pharmaceutics

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Backscattering

With k (dh) :dh = detector height

With :d = particle mean diameterφ = volume fraction

l*=k’(d/φ)

Transport length of the photon

Multiple Light Scattering

BS=k(1/l*)

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® ESTAPOR latex suspension (polystyrene in water) d = 0.3µm, np = 1.59, nf = 1.33, Wavelenght = 880nm

0

20

40

60

80

100

0,0001 0,001 0,01 0,1 1 10 100Volume fraction (%)

Flux

(%)

T(%)

BS(%)

Model

Model

Multiple Light Scattering

DILUTEDREGIME

CONCENTRATEDREGIME

- Effect of the volume fraction-

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®Multiple Light Scattering

Latex suspensions from ESTAPOR (polystyrene in water) φφφφ = 1%, np = 1.59, nf = 1.33, Wavelength= 880nm

0

20

40

60

80

0,01 0,1 1 10 100 Diameter (µm)

BS

(%)

Experiment

Model

- Effect of the particle size -

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®Principle of measurement

Measurement of fast destabilisations

Analysis of diluted to concentrated products

High vertical resolution

Acquisition of the :- Transmitted flux (T)

and- Backscattered flux (BS)

1 Acquisition every 40 µm

One scan lasts 20 seconds

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® One scan

Height (mm)

Back

scat

terin

g (%

)

Acquisitiontime of

each profile

Height (mm)

Multi scans

Principle of measurement

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Particle size variation

Coalescence or flocculation

Particle migration

Sedimentation or creaming

t=0 min

t=15 min

t=0 min

t=15 min

Principle of measurement

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®Parenteral emulsions

o Total Parenteral Nutrition (TPN) emulsionslipid (base emulsion)glucoseamino-acidsvitamins

o Formulated in hospital and tailored upon patient health requirements

o Need to be highly stable for time of delivery

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®Parenteral emulsions

V. Baradel, H. Constant, F. Falson, F. Pirot “Study of Parenteral Emulsion Stability using the Optical Analyzer Turbiscan®”, Pharmaceutical Science Fair 2005

0mm 20mm 40mm 60mm

10%

20%

30%

40%

50%

60%

70%

80%j

1j

2j

5j

5j

7j

8j

8j

12j

CLARIFICATION

CREAMING

Fig.2 : Typical backscattering versus sample height and time for the clarification and the creaming of TPN mixtures. Experiment duration : 12 days, température : 37°C.

0

0,5

1

1,5

2

2,5

3

0 5 10 15 20 25 30 35 40

TPN 1TPN 2TPN 3TPN 4

TPN 5TPN 6TPN 7

Temperature (°C)

Fig.3 : Linear relationship between the kinetic of clarification of TPN mixtureand the temperature of storage.

Stability profile of TPN emulsion Effect of temperature on clarification

Creaming is exponentially dependent on temperature and time of storage

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-Effect of antibiotic on injectable emulsions-

Effect of an additive on the stability of injectable emulsions

The antibiotic (amphotericin) has a small effect on theemulsion C, and a more important one on the emulsions from other suppliers (A, B and D)

With antibiotic

Without antibiotic

Parenteral emulsions

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® o Mainly used as anti-inflammatory agents (corticosteroids)

o Main destabilisationssedimentationflocculation

o Need to be homogeneously redispersible

Ophthalmic suspensions

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®Ophthalmic suspensions

B. Klinke, R. Süverkrüp « Sedimentation characterisation of dexamethasone ophthalmic suspensions by near infrared turbidimetry »

0.1% dexamethasone

0.1% dexamethasone

+ 0.01% benzalkonium chloride

0.1% dexamethasone

+ 0.01% polysorbate 80

Shape of sedimentation profiles informs on the aggregation behaviour

-Sedimentation of dexamethasone suspension-

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® o Application: Asthma treatmento Working principle

o Requirements for high and constant qualitySame dose each time (25-150µL)Same amount of active per dose

Pressurized Metered Dose Inhaler

Evaporation of the propellant10-40µm

5 µm

Drug particles into lungs

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o Turbiscan analysis :Sample in crimped cell

Measurement in fixed position at the bottom and the top to follow fast destabilisation

o Comparison with Timed Medication Delivery (TMD): measurement of the delivered dose

Pressurized Metered Dose Inhaler

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Creaming of the drug insufficient dose after 30s

-Formulation 1 creaming-

0

0,1

0,2

0,3

0,4

0,5

0 5 10 15 20 25 30

Time (s)

Del

ta B

S (%

)

0

20

40

60

80

100

120 Measured dose (%

)BottomTMD

N. Govind, S. Liljedahl,“Assessment of pressurized metered dose inhaler suspension formulations using the Turbiscan”, Respiratory Drug Delivery VIII, 2002

Pressurized Metered Dose Inhaler

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-Formulation 2 sedimentation-

Sedimentation of the drug too much dose after 30s

0

0,15

0,3

0,45

0,6

0,75

0 5 10 15 20 25 30

Time (s)

Del

ta B

S (%

)

050100150200250300350 M

easured dose (%)

BottomTMD

N. Govind, S. Liljedahl,“Assessment of pressurized metered dose inhaler suspension formulations using the Turbiscan”, Respiratory Drug Delivery VIII, 2002

Pressurized Metered Dose Inhaler

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®-Automated analyses-

• Automatic handling with robot (80 runs per hour)

• Automatic data processing on whole group of samples

• Automatic sorting of samples with warning level

• Automatic reporting

Long term stability analysis

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®Conclusion

o Easy to use

o Reliable

o Time saving

o Objective

The Turbiscan® technology is:

So you have more time and information to focus on formulation