Particle Size Method Development and Validation in Support of NanoCrystal Colloidal Dispersion Formulation Characterization

Transcription

1 Particle Size Method Development and Validation in Support of NanoCrystal Colloidal Dispersion Formulation Characterization Webinar Sponsored By: August 2010 Joost Strasters

2 Overview Background: NanoCrystal Colloidal Dispersion Compositions Relevance of particle size analysis Particle size method development and validation 2

3 Background Advances in Drug Discovery (e.g. High Throughput Screening) produce 30%-50% poorly water soluble leads Formulation Approaches Inadequate to Overcome: Poor Bioavailability Food Effects Slow Absorption Safety Issues for IV 3

4 NanoCrystal Technology What is it? A proprietary formulation and manufacturing approach for the delivery of poorly water- soluble drugs Most dosage forms possible (e.g. oral, parenteral and nasal) Increases oral bioavailability & fed/fasted variability Decreases time to onset of action High drug loading possible (up to 30-40% active) Combine with other technologies (e.g. controlled release) Low viscosity liquid preparations Potential for improved chemical stability compared to solutions Uses standard pharmacopoeial materials NanoCrystal technology involves reducing drug particles to to the the nanometer size. By By reducing particle size, we we increase the the drug s exposed surface area. We We then stabilise the the particles to to maintain the the formulation s particle size. 4

5 NanoCrystal Particles Increase Surface Area Total surface area 6 square inches Total surface area 12 square inches Total surface area 24 square inches 5

6 Morphology of NanoCrystal Suspensions 1.0 um 6

7 How are they Made? Rotating Impeller Attrition Media Ball or Media Mill Drug Slurry 7

8 NanoCrystal Technology Stable nanoparticles of poorly soluble drugs typically less than 2,000 nanometres (nm) in diameter can be produced using various approaches such as wet milling, homogenisation, precipitation and supercritical fluid techniques. The wet-milling size reduction process utilizes high energy ball milling with agitator bar Wide range of stabilizers including surfactants and polymers Worked on a broad range of insoluble actives 8

9 NanoMill Media Mill 0.3L 9

10 NanoMill Zeta Mill 10L 10

11 NanoCrystal Colloidal Dispersion Manufacturing Process 11

12 Equipment vs. Development Stage Stage Phase I Mill NanoMill -Z2 Min. API required per batch (kg) 1 Phase II NanoMill -Z Phase III Commercial NanoMill -Z10/ NanoMill -Z60 NanoMill -Z

13 NanoCrystal Colloidal Dispersion formulation to Solid Dosage Form NanoCrystal Colloidal Disperson Formulation Spray Coat Onto Sugar Beads Spray Dry With Sugar Solution Sugar Bead NanoCrystal Particles Dispersed Throughout Sugar Bead NanoCrystal Particles on Drug Coating Low Loading Uniform Dosage Units High Loading Suitable for incorporation into final dosage form 13

14 Analytical Challenges Particle size characterization static light scattering (laser diffraction) emphasis on precision Solid dosage forms: dissolution vs. re-dispersability 14

15 Characterization of Particle Size Distributions Summarize observed distribution with a small number of characteristic values: 1) D mean ; mean diameter, center of gravity 2) Mode; diameter corresponding to maximum 3) Median; 50% point (50% of area above and below)

16 Characterization of Particle Size Distributions: Percentiles frequency D 5 D 10 D 50 size (nm) D 90 D 95 16

17 Change in Particle Size Distribution during Milling f (%) Time (h) Size (μm) 17

18 In-process particle sizing Particle Size Reduction 600 Mean Particle Size (nm) Process Time (min) 18

19 NanoCrystal Colloidal Dispersion Formulation Scale-up Horiba Particle Size (nm) D50 D LMZ-2 LMZ-4 LMZ-10 LMZ-60 LMZ Media Mill Scale 19

20 Monitoring Formulation Stability Dmean (nm) oc 25 oc 40 oc Time (months) 20

21 Redispersibility of Spray Processed NanoCrystal Particles incomplete redispersibility complete redispersibility 21

22 Redispersibility of Spray Processed NanoCrystal Particles NanoCrystal Colloidal Dispersion composition in Redispersibility Medium Non-Optimized NanoCrystal Solid composition in Redispersibility Medium Optimized NanoCrystal Solid composition in Redispersibility Medium 22

23 Particle sizing: Method Development Dispersant Concentration Optimization Agitation/Circulation 23

24 Concentration Optimization Dmean (nm) % Transmittance 24

25 Instrumental Conditions Exp # Agitation Circulation D mean (nm) D 10 (nm) D 90 (nm) Parameters Selected: Agitation: 2 Circulation: 2 25

26 Particle sizing: Method validation Precision instrument inter-assay intermediate Selectivity Robustness 26

27 Particle Sizing: Precision Design of Intermediate Precision Experiments 1 N = 6 Assays Day-1 Analyst-1 Instrument-1 2 N = 6 Assays Day-1 Analyst-2 Instrument-1 3 N = 6 Assays Day-1 Analyst-1 Instrument-2 4 N = 6 Assays Day-1 Analyst-2 Instrument-2 5 N = 6 Assays Day-2 Analyst-1 Instrument-1 6 N = 6 Assays Day-2 Analyst-2 Instrument-1 7 N = 6 Assays Day-2 Analyst-1 Instrument-2 8 N = 6 Assays Day-2 Analyst-2 Instrument-2 27

28 Particle Sizing: Intermediate Precision LA910 Grand RSD Analyst Day Instr.# Replicate Dmean (nm) D5(nm) D10(nm) D50(nm) D90(nm) D95(nm) Grand RSD Dmean (nm) D5(nm) D10(nm) D50(nm) D90(nm) D95(nm) Average STDEV % RSD RSD limit 6% 10% 10% 6% 10% 10% 28

29 Instrument to instrument variability LA910: Formulation samples 6-8 Instruments: Formulation Dmean D10 D50 D90 Dmean D10 D50 D90 sd (nm) sd (nm) sd (nm) sd (nm) rsd (%) rsd (%) rsd (%) rsd (%) A B C D E F

30 Particle Sizing: Precision (Repeatability) LA950 Instrument 1: Instrument 2: Formulation 1 Dmean D5 D10 D50 D90 D Average Std Dev RSD Formulation 1 Dmean D5 D10 D50 D90 D Average Std Dev RSD

31 Instrument to instrument variability LA950: Formulation samples 4 Instruments: Formulation 1 Dmean D5 D10 D50 D90 D95 Average (nm) Std Dev (nm) RSD (%) Formulation 2 Dmean D5 D10 D50 D90 D95 Average (nm) Std Dev (nm) RSD (%)

32 Selectivity LA950: Formulation Target Analysis Range large Dmean (nm) medium small %Transmittance 32

33 Selectivity LA950: Formulation 2 Target Analysis Range Mean Particle Size (nm) % Transmittance 33

34 Robustness LA950 Method Parameter A B C D E F G Mean Particle Size (nm) DOE Pattern Agitation Circulation Waiting Time Sampling Times % Transmittance Temperature of Dispersant *

35 Robustness LA950 Method Key Agitation Level Setting Circulation Level Setting Waiting Time (Sec) Sampling Times % Transmittance Temperature ( o C) * Method Value Ambient * Max (+1) Value Ambient + 4 O C * Min (-1) Value Ambient - 4 O C * Particle Size Measurement Main Effect (D value) Standard Deviation (SD) of Main Effects * 5 SD x 2 7 Main Effect Considered Significant [(P<0.05) if D > (SD x 2)] (Y/N) No No No No Yes No * 35

36 In-Process Particle Sizing Particle Size (nm) D Dmean Time (min) 36

37 In-Process Particle Sizing Particle Size (nm) D Time (min) Dmean 37

38 Conclusion Particle size analysis of NanoCrystal Colloidal Dispersion Formulations by means of static laser light scattering is successfully used for: Process control for manufacture Monitoring formulation stability Characterizing formulation performance Technology Transfer Crucial method characteristics: Intermediate precision Robustness 38

39 SUMMARY Elan Drug Technologies The World s Leading Drug Delivery Company Top Drug Delivery Company of the Decade -Drug Delivery Technology Survey, May 2010 For more information go to our website 39

40 For More Details Visit Contact HORIBA directly at Visit the Download Center to find this recorded presentation and many more on other topics 40