REUNION ARMOR Etude de la surface de particules de Lactose

Identification of contaminants on excipients using Ultrasound Acoustic-AFM Impact on the interactions drug-carrier

Cedric [email protected]

ICB UMR CNRS 6303 – University of Bourgogne

CONTEXT 2

1. Context2. UA-AFM

- Concept- Results

3. Interactions drugs/lactose- Concept- Results

4. Conclusion

Pure lactose Pharmaceutical lactose

Lots of knowledge about lactose Interactions with active ingredients API not perfectly understoodVery few studies exist on particle surface

Usual techniques could not address the issue! (XPS, XRF, XRD, Raman, SIMS…)

Development of UA-AFM (Ultrasound Acoustic – AFM)

Ultra-purification industrially and commercially non viableImpurities are only on the surface of lactose particles

Interaction with active substances take place only on the surface

Big differences between pure lactose and pharmaceutical grade lactose

Impurities = lactulose, glucose, galactose and riboflavin

3

UA-AFM

1. Context

2. UA-AFM- Concept- Results


4. Conclusion

2UA-AFM CONCEPT 4

1. Context



4. Conclusion

Signal processing

Topographicimage

Acousticphaseimage

Acousticamplitude

image

2UA-AFM CONCEPT 5

1. Context



4. Conclusion

Investigation depth increase with frequency difference sub-surface analysis

Originally developed for local echography (bacteria, yeast)

Non-destructive investigation of organic and inorganic materials

Density sensitive technic

Frequency difference fixed in this problematic(investigation depth < 100nm)Comparison between 2 food grade lactoses and 5 pharmaceutical grade lactoses

Density(g.cm-3)

STD(g.cm-3)

Lactose 1.53 0.0003

Lactulose 1.59 0.004

Glucose 1.56 0.0001

Galactose 1.62 0.0001

Riboflavine 1.36 0.001

Helium pycnometry results

2PHARMACEUTICAL GRADE LACTOSES 6

1. Context

2. UA-AFM- Concept

- Results3. Interactions

drugs/lactose- Concept- Results

4. Conclusion

No relationship between topography and acoustic response

Characteristics crystallographic stairtreads of lactose does not respond differently200 particles analyzed by batch

2µm

Glucose,

Galactose,

Lactulose

Lactose

Lactose

Riboflavin

2µm2µm 2µm

2RESULTS ON DIFFERENT GRADE LACTOSES 7

1. Context

2. UA-AFM- Concept

- Results3. Interactions

drugs/lactose- Concept- Results

4. Conclusion

More than 50% of the particle surface is covered with impurities (excluding lactose P2)

For couples P1-P3 and P4-P5, they have same accessible surface to drugs but withdifferent contaminants distribution:Impact on interaction with drugs?

Sieved particles more homogeneous in size and accessible surface

Difficulties to separate the acoustic response of glucose, galactose and lactulose

Variable presence of riboflavin

8

Interactions drug/lactose

1. Context2. UA-AFM

- Concept- Results

3. Interactions drug/lactose- Concept- Results

4. Conclusion

2SURFACE FORCE SPECTROSCOPY (SFS) 9

Surface Force Spectroscopy modeFunctionalized tip with a particle of active ingredient (API)Force applied on the sample fixed16384 force curves on 25µm² repeated 10 times on each pure compound

5µm128 force curves

1. Context2. UA-AFM

- Concept- Results


4. Conclusion

In the literature, only interactions with pure lactose are studied Not representative of the real case Need to use the results in UA-AFM

2INTERACTIONS FLUTICASONE PROPIONATE / LACTOSE 10

Impurities decrease by a factor 10 the adhesion between fluticasone propionate and lactose (results from 820000 force curves)

Impurities affect completely the interactions

1. Context2. UA-AFM

- Concept- Results

3. Interactions drug/lactose- Concept

- Results4. Conclusion

2INTERACTIONS SALBUTAMOL SULFATE / LACTOSE 11

1. Context2. UA-AFM

- Concept- Results



Impurities decrease by a factor 2 to 6 the adhesion between salbutamol sulfate and lactose (results from 820000 force curves)

Salbutamol sulfate less sensitive to the presence of glucose but verysensitive to riboflavin

2INTERACTIONS SALMETEROL XINAFOATE / LACTOSE 12

Impurities decrease by a factor 2 the adhesion between salmeterol xinafoate and lactose except for glucose (results from 820000 force curves)

Salmeterol xinafoate less sensitive to the presence of glucose

1. Context2. UA-AFM

- Concept- Results



2CONCLUSIONS 13

1. Context2. UA-AFM

- Concept- Results


4. Conclusion

Possible to measure accessible surface to active ingredients for the 1st time

Highly sensitive to density variations

Allow topography of the surface and chemical identification of contaminants with a single non-destructive technique

◊ Ultrasound acoustic AFM:

◊ Interaction drug/carrier:

AFM can measure interactions between an active substance and the different compounds of a lactose Comparative values

Results provide a real plus in understanding interactions lactose/API

Important to understand interactions drug/carrier for the next-generation of inhalation drugs (vaccines…)

May be the small accessible surface can explain low FPF with DPI

14

THANK YOU FOR YOUR ATTENTION

Cedric [email protected]

8.5 V12.1 V

2IMPROVE ON IMAGE TREATMENT 15

Lactulose vs. Galactose Lactulose vs. GlucoseDensity(g.cm-3)

Standarddeviation(g.cm-3)

Lactose 1.53 0.0003

Lactulose 1.59 0.004

Glucose 1.56 0.0001

Galactose 1.62 0.0001

Riboflavine 1.36 0.001

A lot improvement has been made on the live processing and post-processing signals

Significant sensitivity to variation in density

Acoustic results on binary mixture

Lots of experiments has been made to understand the interaction between the acoustic wave and the tip (not presented – confidential)

2UA-AFM CONCEPT 16

Equation of surface’s wave:

𝑆 𝑡 = 𝐴 𝑧 [cos ∆𝜔𝑡 + ∆𝜑 + cos ∆Ω𝑡 + ∆Φ ]

𝐴 𝑧 = 𝐴0𝑒−𝛼.𝑧

𝑣With:

Allow 3D reconstruction with image stacks

Δf = 40 kHz

Δf = 39 kHz

Δf = 37 kHz

Topography

1. Context



4. Conclusion

Investigation depth increase with frequency difference sub-surface analysis

Originally developed for local echography (bacteria, yeast)

Non-destructive investigation of organic and inorganic materials

Density sensitive technic

Documents

REUNION ARMOR Etude de la surface de particules de Lactose