Particle Engineering of Poorly Water Soluble Drugs by Controlled

Chapter 19

Particle Engineering of Poorly Water Soluble Drugs by Controlled Precipitation E. J. Elder , J. E. Hitt , T. L. Rogers , C. J. Tucker , S. Saghir , G. B. Kupperblatt , S. Svenson , and J. C. Evans

Downloaded by UNIV OF GUELPH LIBRARY on July 6, 2012 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch019

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Dowpharma, Chemical Sciences, and Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674 Current address: Mylan Technologies, 110 Lake Street, St Albans, V T 05478 Current address: Dendritic Nanotechnologies, 2625 Denison Drive, Mt. Pleasant, MI 48858 4

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Controlled precipitation is a particle engineering technology under development for enhancing the aqueous dissolution rate and bioavailability of poorly water soluble drugs. Experiments with danazol and other model drugs showed that in vitro solubilization rate and in vivo absorption of the drug were improved by this technology.

Introduction Many active pharmaceutical ingredients (API) suffer from low bioavailability due to poor solubility and/or poor dissolution rates in water (1,2). The preferred way to improve the solubility is to increase the surface area of the API particles, which is accomplished by reducing the particle size. A commercial technique for producing crystalline drug nanoparticles involves wetmilling the drug particles for extended times in the presence of stabilizers (3). However, this approach is limited to water-soluble stabilizers with low viscosity, and there is a risk of contamination from milling media. In addition, milling may reduce the degree of crystallinity of the drug particles (4).

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© 2006 American Chemical Society

In Polymeric Drug Delivery II; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

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Various precipitation techniques have been employed in pharmaceutical applications (5-14). Controlled precipitation is a particle engineering technology under development for enhancing the aqueous dissolution rate and bioavailability of poorly water soluble drugs (15). This process involves precipitating the drug into an aqueous solution in the presence of crystal growth inhibitors to form drug nanoparticles. Advantages and features include: • • • •

Crystalline drug particles from molecular solution enable a polish filtration. Process is fast and scalable with conventional process equipment. Levels of residual solvents are low. Excipients used are generally pharmaceutically acceptable.

This paper describes preparation of three model drugs (danazol, naproxen, and ketoconazole) by controlled precipitation and presents the resulting in vitro dissolution and in vivo bioavailability in dogs.

Materials and Methods Materials Table I lists the characteristics of the three model drugs. Crystal growth inhibitors included poloxamer 407, polyvinyl pyrrolidone, and polyvinyl alcohol, all pharmaceutically acceptable excipients.

Table I. Properties of Model Drugs Danazol, Naproxen, and Ketoconazole Property Activity Melt point, °C Particle size, um Aqueous solubility, mg/mL (25°C)

Danazol androgenic steroid 226 ~5 0.001

Naproxen NSAID/analgesic 152 -15 0.023

Ketoconazole antifungal 150 -25 0.017

Assessment of commercial ketoconazole tablets (Nizoral, Janssen-Ortho, Lot 93P0241E) was also conducted in this study.


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Process Description Figure 1 illustrates the controlled precipitation process. Table II gives the experimental parameters for the three model drugs. The model drug and the crystal growth inhibitor (CGI) were dissolved in methanol, and in the case of ketoconazole, crystal growth inhibitor was also dissolved in the water phase. The organic phase was precipitated into chilled water. The controlled precipitation process was conducted in a continuous manner allowing for slurry concentration and solvent removal. The evaporated solvent was recovered. The concentrated, solvent-stripped slurry was then freeze-dried (lyophylized) in the case of laboratory-scale drying or spray-dried in the case of pilot-scale drying to remove the aqueous phase and isolate the nanostructured crystalline drug substance (modified model drug).

Figure 1. Process diagram for controlled precipitation. (Adapted with permission from Reference 15. Copyright 2004 Springer Science and Business Media, Inc.)

Characterization The modified model drugs were characterized by scanning electron microscopy (SEM) and x-ray diffraction (XRD). Particle size was determined by dynamic light scattering. Dissolution rates were determined using U S P apparatus II (paddles) with an aqueous media containing 0.75% sodium lauryl sulfate and 1.21% TRIS at p H 9.0. Bioavailability was determined in beagle dogs as described for two of the drugs in their respective sections.


295 Table II. Experimental Parameters for Controlled Precipitation Parameter Organic phase C G I Ratio drug:CGI Water phase CGI and level Ratio organic:water during precipitation

Danazol poloxamer 407 2:1

Naproxen polyvinyl pyrrolidone K30 2:3

1:5

1:5

Ketoconazole polyvinyl pyrrolidone K 3 0 1:0.5 polyvinyl alcohol, 0.61% 1:5


C G I = crystal growth inhibitor

Results and Discussion When the dissolved drug is precipitated in the presence of a crystal growth inhibitor, the inhibitor adsorbs on the crystal surface shortly after nucleation, hindering solute mass transport with the following results: • • •

Nucleation dominates growth in the relief of supersaturation. Mean crystal size is depressed. Slurry can be recycled with little growth on existing crystals.

Danazol Figure 2 shows SEMs of bulk danazol compared to the modified danazol. Particle size was reduced from 5 um to 0.46 um as determined following redispersion of the agglomerated nanostructured particles prepared by controlled precipitation. X-ray diffraction analysis indicated that the modified danazol was crystalline (Figure 3). Residual solvent level in the modified danazol powder was less than 250 ppm, which is well below I C H guidelines for methanol (3000 ppm).

In Vitro Dissolution Dissolution of both danazol U S P (micronized) powder and a physical blend of danazol U S P and excipients required 30 minutes to reach 90% (Figure 4). In



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Figure 2. Scanning electron micrographs of as-received bulk danazol (5 pm scale) and agglomerated danazol (2 pm scale) prepared by controlled precipitation, which rapidly redisperse in water to 0.46 pm primary particles. (Reproduced with permission from Reference 15 and 16. Copyright 2004 Springer Science and Business Media, Inc. and Drug Delivery Technology LLC)

As-received bulk danazol

Danazol prepared by controlled precipitation

Figure 5. X-ray diffraction analysis of as-received bulk danazol and danazol prepared by controlled precipitation.


297 comparison, the modified danazol powder prepared by controlled precipitation was 100% dissolved within 5 minutes.


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Figure 4. Dissolution of danazol (n=6). (Reproduced with permission from Reference 16. Copyright 2004 Drug Delivery Technology LLC.)

Bioavailability The danazol powder prepared by controlled precipitation showed substantially improved bioavailability (Figure 5) compared to the drug asreceived (micronized danazol USP). Tablets prepared on a Carver press from modified danazol (equivalent to 200 mg danazol) formulated with microcrystalline cellulose and carboxymethylcellulose (47.5:47.5:5) showed further enhancement in bioavailability. The increased bioavailability observed with the control is due to an excipient effect that enhances wettability of the powder.

Naproxen Figure 6 shows SEMs of bulk naproxen compared to the modified naproxen. Particle size was reduced from 17 p to 4 pm. X-ray diffraction analysis indicated that the modified naproxen was crystalline (Figure 7). Residual solvent level in the modified naproxen powder was approximately 150 ppm, which is well below I C H guidelines for methanol (3000 ppm).



Figure 5* Mean plasma levels ofdanazol in dogs. (Reproduced with permission from Reference 16. Copyright 2004 Drug Delivery Technology LLC)


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Figure 6. Scanning electron micrographs (5 pm scale) of as-received bulk naproxen and naproxen prepared by controlled precipitation. (Adapted with permission from Reference 15. Copyright 2004 Springer Science and Business Media, Inc.)

As-received bulk naproxen

Naproxen prepared by controlled precipitation

Figure 7. X-ray diffraction analysis of as-received bulk naproxen and naproxen prepared by controlled precipitation.

In Vitro Dissolution Dissolution of as-received naproxen was less than 60% at 60 minutes. In comparison, the modified naproxen powder prepared by controlled precipitation and either freeze-drying (lab-scale) or spray-drying (pilot-scale) was 95 to 100% dissolved within 20 minutes. Bioavailability of naproxen was not measured.


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Figure 2. Dissolution of naproxen (n=6).

Ketoconazole Figure 8 shows SEMs of bulk ketoconazole compared to the modified ketoconazole. Particle size was reduced from 15 um to 7 urn for freeze-dried (lab-scale) ketoconazole by precipitation and 2 um for spray-dried (pilot-scale) ketoconazole by precipitation. X-ray diffraction analysis indicated that the modified ketoconazole was crystalline (Figure 9). Residual solvent level in the modified ketoconazole powder was well below I C H guidelines.

In Vitro Dissolution Dissolution of ketoconazole as-received powder was less than 60% at 60 minutes (Figure 10). Ketoconazole by precipitation was greater than 80% dissolved within 10 minutes and 100% dissolved within 60 minutes. In comparison, dissolution of the commercial tablet was approximately 70% at 60 minutes.



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Figure 8. Scanning electron micrographs of as-received bulk ketoconazole (20 pm scale) and ketoconazole prepared by controlled precipitation (5 pm scale).

As-received bulk danazol

Danazol prepared by controlled precipitation

Figure 9. X-ray diffraction analysis of as-received bulk ketoconazole and ketoconazole prepared by controlled precipitation.


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Figure 10. Dissolution of ketoconazole (n=6).

Bioavailability Ketoconazole prepared by precipitation showed improved bioavailability over both ketoconazole as-received and a blend of ketoconazole as-received with excipients in capsules (Figure 11). Further improvement was seen when the modified ketoconazole was formulated in capsules or tablets. The capsules were prepared by blending the modified ketoconazole (equivalent to 200 mg ketoconazole) with microcrystalline cellulose and carboxymethylcellulose (47.5:47.5:5) and hand-filling into size 0 gelatin capsules. The tablets were formulated in the same manner and compressed manually on a Carver press.

Conclusions Controlled precipitation is a viable particle engineering technology for enhancing the bioavailability of poorly water soluble drugs. Demonstration with danazol and other model drugs resulted in substantial improvements to in vitro dissolution and in vivo bioavailability.



Figure IL Mean plasma levels of ketoconazole in dogs.


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Acknowledgements The authors gratefully acknowledge the laboratory support contributions provided by Analytical Sciences and BioAqueous Solubility Services at Dow. BioAqueous is a service mark of The Dow Chemical Company. SM


References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

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Particle Engineering of Poorly Water Soluble Drugs by Controlled

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