Solidification of Nanosuspension via Spray GranulationYidan Lan1, Srikanth Kakumanu2, Carl Beckett2, Nigel Langley11 BASF Corporation, Pharma Ingredients and Services, 500 White Plains Road, NY 10591

2 Covaris Incorporated, 14 Gill Street, Woburn, MA 01801

yidan.lan@basf.com

IntroductionIn recent years, formulation scientists are facing considerable challenges in finding an effective method to handle poorly water soluble new chemical entities. Although remarkable progresses have been achieved in solid dispersion1, micronization2 and nanoparticle technologies3, many process/formulation related issues need to be further addressed before these platforms can be generalized. For an example, nanoparticle technology has been identified as an important avenue to improve solubility and bioavailability of poorly soluble drugs in suspension, but how to produce a real solid dosage form using nanotechnology remains a top challenge in the following two aspects.

1. How to efficiently prepare nanosuspension without degradation and contaminations.

Although nanotechnologies have been advanced in milling4, homogenization5 and microfluidizer6, a common disadvantage of these processes lies on low yield, labor consuming, and possible contamination, as summarized in Table 1.

Features Mill Homogenizer Microfluidizer AFA

Temperature control no no poor yes

Rapid yes yes yes yes

High Yield no significant loss no yes -100%

Cross Contamination yes yes yes no

Reproducibility yes variability yes yes

Scalability yes imprecise yes yes

Labor consuming yes yes yes no

Automation Platform no customized no yes

Industry Standard yes yes yes no

Table 1. Comparison of technologies in preparation of nanosuspension

In this study, an innovative technique, called Adaptive Focused Acoustics™ (AFA)7 developed by Covaris, was utilized to prepare nanosuspension for poorly soluble model drug Ibuprofen.

Different from conventional sonication, AFA system focuses ultrasonic energy into a discrete zone within a vessel, mechanically processing the sample at a frequency 15 to 30 times higher than a regular sonicator (Figure 1a). When an acoustic burst is applied to the focal zone, numerous cavitation bubbles are generated within the sample. After each acoustic burst is ended, these microscopic bubbles collapse, creating intense, localized, high velocity jets of solute (typically water). This process is repeated thousands of times per second, rapidly reducing the particle size of sample in a short duration (Figure 1 b). Therefore, the major advantages of AFA over the conventional approaches are shorter processing time at a lower isothermal temperature, and producing narrow size distribution nanoparticles without contamination.

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Cinnarizine 250ml 5mg/ml0.1% SLS 0.025% MC

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Figure 1. (a) A schematic diagram of AFA. (b) An example of particle size reduction during AFA process.

2. How to efficiently solidify the suspension to make better tablet and capsules.

Freeze drying8 and spray drying9 have been widely used to convert nanosuspension into solid form. To overcome the high cost and low efficiency of these processes, spray granulation and beads coating of nanosuspension have emerged recently as a major trend10. In this study nanoparticles prepared by AFA process were spray coated onto microcrystalline cellulose beads in a fluid bed, which provides following advantages:

■ Beads coating consumes less energy than spray drying and freeze drying.

■ Almost uniform particle size distribution with better flowability

■ Coated beads are more suitable for capsules filling or direct compression.

Experimental MethodsNonsuspension preparation by AFAFocused-ultrasonicators Model S220X with AFA technology (Covaris Inc, Woburn, Massachusetts, USA) was used in preparation of nanoparticles. A schematic diagram of the multi-pass process was shown in Figure 3. Ibuprofen 50, provided by BASF (Florham Park, NJ, USA), was processed at a concentration of 50mg Ibuprofen per ml. The batch size is 250ml, and test was performed at 3ºC with the help of a chiller. AFA process employed a center frequency of around 500 kHz, corresponding to a wavelength of about 2 mm. The duty factor is set to 50%, which means the transducer is “On” in 50% of the cycle time, emitting acoustic energy. Peak Incident Power (PIP), representing the intensity of acoustic power transmitted by the transducer per unit area, is adjusted to 300, while the maximum number of cycle is set to 1000.

Figure 3. A schematic diagram of Multi pass flow system

It was found the mixture of Kollidon® 30 (0.1%) (BASF) and SLS (0.006%) (Sigma) was suitable for stabilize the ibuprofen suspension. Considering PVP is not compatible with Ibuprofen11 in stability study, Methyl Cellulose (0.2%) and SLS (1%), both purchased from Sigma, was used for stabilization purpose. The particle size of the suspension was monitored by Zetasizer Nano ZS90 (Malvern, Westborough MA, USA) during the process.

Nanoparticle Solidification by beads coating in Fluid BedFluid bed granulation of nanosuspension was performed using GPCG 1 (Glatt Air Technologies Inc. Ramsey, NJ, and USA). MCC beads (Celphere CP102 Asahi Kasei, Japan) were preheated to 35ºC and coated in a top spray chamber of GPCG1. The process parameters are listed in Table 2.

Process parameters

Batch size 250 g

Inlet air temperature 50 - 54 ºC

Outlet air temperature 32 - 33 ºC

Product temperature 35ºC

Velocity of Air Flow 5m/s

Nozzle Diameter 0.8 mm

Spray rate 4 g/min

Atomizing pressure 1.5 - 2.0 bar

Table 2. Process parameter of Top Spray Fluid Bed (GPCG1)

Drug release was studied using USP apparatus 2, (Distek, 2100C) at 37ºC with paddle speed of 50 rpm. Samples were analyzed by a UV spectrophotometer (Shimadzhu, UV160u) at 221 nm.

ResultsAfter one hour AFA processing, the particle size of Ibuprofen 50 was rapidly reduced from 50 micron to submicron size (Figure 4) with a narrow distribution and peak at 773 nm (Figure 5). It was demonstrated that the time for preparation of suspension was independent of solid concentration when it was below 100mg/ml. In a separate study on particle size distribution of Ibuprofen suspension, it was confirmed that six-hour of AFA process was equivalent to 24 hours process by beads milling (Figure 6) The AFA processed nanosuspension was very stable. Particle size distribution did not have any shift after 72 hours of storage.

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Figure 4. Comparison of microscopy images of particles (a) Unprocessed Ibuprofen 50, (b) Processed Ibuprofen nanosuspension

Figure 5. Particle size distribution measured by Malvern Zetasizer Nano ZS90 after one hour of AFA processing.

Figure 6. Comparing bead Milling to AFA process on particle size distribution

The capability of drying Ibuprofen nanosuspension in fluid bed spray granulation has been determined in this study. The coating process was easy to control, and the coated beads were uniform without agglomeration. Comparing to the unprocessed Ibuprofen, the beads produced from spray coating of Ibuprofen nanosuspension have demonstrated a faster dissolution profile. This is mainly due to the dispersion of the nanoparticles. It was observed that the dissolution rate of Ibuprofen nanasuspension coated beads was 28% faster than that of the unprocessed Ibuproben in the first 5 minutes as shown in Figure 7.

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Figure 7. Dissolution rate comparison of nanosuspension coated beads and unprocessed ibuprofen.

Conclusions ■ Demonstrated the feasibility of combining AFA technology and spray granulation

■ AFA could efficiently produce Ibuprofen nanoparticles.

■ Stable nanosuspension with narrow size distribution could be directly used for beads coating.

■ Drying nanosuspension via spray granulation is an efficient method for screening formulations.

■ Coated beads with excellent flowability could be compressed into tablets or filled into capsules.

■ Further study on AFA processed nanoparticles for functional coating.

References

1. K. Kolter et al. Hot-Melt Extrusion with BASF Pharma Polymers, Extrusion Compendium, 2nd edition, BASF, (2012)

2. A. Martín. MJ. Cocero, Adv. Drug Deliv. Rev.;60(3):339-50, (2007)

3. B. Van Eerdenburgh et al, Eur. J. Pharm. Sci. 35, 344-359 (2008)

4. T. Niwa et al, Int J. Pharm. 58, 173-82 (2008)

5. A.A. Noyes et al, J. Am. Chem. Soc. 19, 930-34, (1997)

6. HS. Ali et al, J. Control. Release 149(2):175-81(2011)

7. Jr. Laugharn et al. US patent 7,687,039, (2010)

8. IS Ahmed et al, Eur. J. Pharm. Sci. 32(1), 58-68 (2007)

9. T. Niwa et al, Pharm. Res. 28, 2339-49, (2011)

10. P. Kayaert et al, J. Pharm. Pharmacology, 63, 1446-53 (20011)

11. Ibuprofen Technical Information, Pharma Ingredients & Services, BASF (2006)

AAPS Annual Meeting, Chicago, 2012

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Variable Reservoir

Ibuprofen(50mg/ml)

Multi pass flow system

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