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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
3. Interactions drugs/lactose- Concept- Results
4. Conclusion
2UA-AFM CONCEPT 4
1. Context
2. UA-AFM- Concept- Results
3. Interactions drugs/lactose- Concept- Results
4. Conclusion
Signal processing
Topographicimage
Acousticphaseimage
Acousticamplitude
image
2UA-AFM CONCEPT 5
1. Context
2. UA-AFM- Concept- Results
3. Interactions drugs/lactose- Concept- Results
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
3. Interactions drug/lactose- 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
3. Interactions drug/lactose- Concept
- Results4. Conclusion
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
3. Interactions drug/lactose- Concept
- Results4. Conclusion
2CONCLUSIONS 13
1. Context2. UA-AFM
- Concept- Results
3. Interactions drug/lactose- 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
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
2. UA-AFM- Concept- Results
3. Interactions drugs/lactose- Concept- Results
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