Size characterization of micelles and microemulsions

Size characterization of micelles and microemulsions by Taylor dispersion analysis Dr HDR Vincent Jannin, ACS Division of Colloid and Surface Chemistry, Aug. 23rd, 2018

COLL 789

LIPID-BASED FORMULATIONS

Type

Composition

Comments

I

Lipids

Not self-emulsifying, digestion required

II

Lipids + water-insoluble surfactants

Self-emulsifying, high lipid

III

Lipids + surfactants + co-solvents

Self-emulsifying, lower lipid

IV

Water-soluble surfactants + co-solvents Formation of micelles

Koziolek, M. et al. 2018. Pharm Res https://doi.org/10.1007/s11095-017-2289-x

2

MECHANISMS OF SELF-EMULSIFICATION

Oil / water-soluble surfactant mixture (Type III): Aqueous phase Lipidic phase Hydrosoluble components ○ Mechanism of self-emulsification by diffusion and stranding

Oil / surfactant mixture with limited solubility in water (Type II): Phase aqueuse Aqueous phase Phasephase lipidique Lipidic Phasecrystalline liquide cristalline Liquid phase Mechanism of self-emulsification by formation of a lamellar liquid crystalline phase

Labrafil droplet (PLM) 3

SELF-EMULSIFICATION OF LABRAFIL® M2125CS

Jannin, V., Bruley, C. 2007. Self-emulsification of Labrafil M 2125 CS. DOI: 10.13140/RG.2.2.14401.25441

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TERNARY PHASE DIAGRAM Transparent dispersion (450 nm) Miscible / Non homogeneous dispersion

* Water-soluble surfactant: Kolliphor® RH40 * Water-insoluble surfactant: Capryol® 90 * Oil: Maisine™ CC

% Maisine 35-1 5

TAYLOR DISPERSION ANALYSIS Principle

Chamieh, J., Davanier, F., Cottet, H. 2015 Application of TDA for the sizing of micelles. Unpublished report

6

TAYLOR DISPERSION ANALYSIS


7



8



9

TAYLOR DISPERSION ANALYSIS 2. 𝐷 𝑅𝑐2 𝑢 𝐻= + 𝑢 24. 𝐷

𝐷=

𝑅𝑐 2 .𝑡𝑚 24.𝜎²

𝑘𝐵 . 𝑇 𝑅ℎ = 6. 𝜋. 𝐷. 𝑛0

Taylor-Aris equation

s D = Molecular diffusion coefficient (m².s-1) Rc = Capillary radius (m) tm = Peak variance time (s) s² = Peak variance (s²) kB = Boltzmann constant (m².kg.s-2.K-1) T = Temperature (K) h0 = Dynamic viscosity (Pa.s) u = Linear mobile phase velocity (m/s)

tm



Dt0  1.25 2 Rc

Pe 

uRc  40 D


10

TDA – PLUG MODE & UV

Chamieh, J., Davanier, F., Jannin, V., Demarne, F., Cottet, H. 2015 Size characterization of micelles and microemulsions by Taylor Dispersion Analysis. Int. J. Pharm. 492(1-2) 46-54.

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TDA – FRONTAL MODE & FLUORESENCE

Chamieh, J., Jannin, V., Demarne, F., Cottet, H. 2016 Hydrodynamic size characterization of a selfemulsifying lipid pharmaceutical excipient by Taylor dispersion analysis with fluorescent detection. 12 Int. J. Pharm, 513. 262-269

GASTROINTESTINAL TRACT - LIPIDS Lipids

Bile (bile salts, cholesterol)

Gastric lipase (HGL)

Pancreatic juice (HPL, HPLRP2, CEH)

Lipolysis in the small intestine Absorption of lipolysis byproducts Bakala N’Goma, J.C., Amara, S., Dridi, K, Jannin, V., Carrière, F. 2012. Understanding lipid digestion in the GI tract for effective drug delivery. Therapeutic Delivery, 3(1) 105-124.

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TDA COUPLED WITH LIPOLYSIS

Chamieh, J., Merdassi, H., Rossi, J.C., Jannin, V., Demarne, F., Cottet, H. 2018 Size characterization of lipid-based self-emulsifying pharmaceutical excipients during lipolysis using 14 Taylor dispersion analysis with fluorescence detection. Int. J. Pharm. 537 (1-2) 94-101

LIPOLYSIS OF LABRASOL® • Labrasol® is not digested by the main pancreatic enzyme • Lipolysis by gastric and minor pancreatic lipases • Digestibility of glycerides and PEG esters

Fernandez, S., Jannin, V., Rodier, J.D., Ritter, N., Mahler, B., Carrière, F., 2007. Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol®, medium chain glycerides and PEG esters. Biochim. Biophys. Acta. 1771. 633-640

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INFLUENCE OF COLLOIDAL STRUCTURE OF LABRASOL® Coacervation at 37°C

No coacervation at 37°C

1

2

3

1,000

A

Labrasol in water 100

10

A

20 15 10 5 0

B TDA Front 37°C DLS 37°C

TDA Front 25°C DLS 25°C

0

10

20

30

40

50

60

70

B 100

Rh (nm)

120

80 60 CEH rDGL

40 20

0

0 10

20

10

20

30

40

50

CLabrasol (g/L)

rHPLRP2

0

• Colloidal structure 100 (1) suspension, 100 (2) coacervate + micellar solution, 10 10 (3) micellar solution Rh (nm)

1

Lipase activity (% of maximum activity)

20 15 10 5 0

Rh DLS/Rh TDA

Labrasol in lipolysis medium

Rh DLS/Rh TDA

Particle size Nicomp Intensity weighted (nm)

10,000

30

40

50

Labrasol concentration (g/L)

60

70

60

70

0

10

20

30

40

50

60

70

CLabrasol (g/L)

• Enzyme activity depends on the colloidal structure of aqueous dispersions

Fernandez, S., Jannin, V., Chevrier, S., Chavant, Y., Demarne, F., Carrière, F. 2013. In vitro digestion of the self-emulsifying lipid excipient Labrasol® by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate. Pharm. Res. 30. 3077-3087 Chamieh, J., Jannin, V., Demarne, F., Cottet, H. 2016 Hydrodynamic size characterization of a selfemulsifying lipid pharmaceutical excipient by Taylor dispersion analysis with fluorescent detection. 16 Int. J. Pharm, 513. 262-269

8x10

-11

7x10

-11

6x10

-11

5x10

-11

4x10

-11

3x10

-11

2x10

-11

1x10

-11

1.2x10 -3

A h (Pa.s)

8.0x10 -4

6.0x10 -4

4.0x10 -4

molecular diffusion coefficient

2.0x10 -4

0

dynamic viscosity

0.0

B

10 8 6 4 2

Peak Area (RFU.min )

average hydrodynamic radius

12

D

50

peak area

-1

14

Rh (nm)

C

1.0x10 -3

2

-1

D (m .s )

LIPOLYSIS OF LABRASOL

40

30

20

10

0

0

20

40

60

Time (min)

80

100

120

0

20

40

60

80

100

120

Time (min)

Chamieh, J., Merdassi, H., Rossi, J.C., Jannin, V., Demarne, F., Cottet, H. 2018 Size characterization of lipid-based self-emulsifying pharmaceutical excipients during lipolysis using 17 Taylor dispersion analysis with fluorescence detection. Int. J. Pharm. 537 (1-2) 94-101

LIPOLYSIS OF GELUCIRE® 44/14 • Gelucire® is not digested by the main pancreatic enzyme • Lipolysis by gastric and CEH • Digestibility of PEG esters with high molecular weight

Fernandez, S., Rodier, J.D., Ritter, N., Mahler, B., Demarne, F., Carrière, F., Jannin, V. 2008. Lipolysis of the semi-solid self emulsifying excipient Gelucire® 44/14 by digestive lipases. Biochim. Biophys. Acta 1781. 367-375. Chamieh, J., Davanier, F., Jannin, V., Demarne, F., Cottet, H. 2015 Size characterization of micelles 18 and microemulsions by Taylor Dispersion Analysis. Int. J. Pharm. 492(1-2) 46-54.

LIPOLYSIS OF GELUCIRE® 44/14 • Gelucire® forms micelles before the addition of lipase • Formation of a lamellar phase (Lα) during digestion.

Vithani, K., Hawley, A., Jannin, V., Pouton, C., Boyd, B. 2017 Inclusion of digestible surfactants in solid SMEDDS formulation removes lag time and influences the formation of structured particles during digestion. AAPS Journal 19(3) 754-764 Chamieh, J., Merdassi, H., Rossi, J.C., Jannin, V., Demarne, F., Cottet, H. 2018 Size characterization of lipid-based self-emulsifying pharmaceutical excipients during lipolysis using 19 Taylor dispersion analysis with fluorescence detection. Int. J. Pharm. 537 (1-2) 94-101

IN VITRO DIGESTION: CINNARIZINE / FENOFIBRATE • Cinnarizine and fenofibrate in crystalline state in SMEDDS can be partially solubilized in situ in the digestion products.

Vithani, K., Hawley, A., Jannin, V., Pouton, C., Boyd, B.J. 2018 Solubilisation behaviour of poorly water-soluble drugs during digestion of solid SMEDDS. Eur. J. Pharm. Biopharm. 130 236-246 20

GRATEFUL ACKNOWLEDGEMENTS TO •

University of Montpellier, France – Pr Hervé Cottet – Dr Joseph Chamieh

• Monash University, Melbourne, Australia - Pr Ben Boyd - Kapilkumar Vithani

[email protected] https://www.researchgate.net/profile/Vincent_Jannin

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