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Emerging Technologies to Increase the Bioavailability of Poorly Water-Soluble Drugs

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Formulating Poorly Water Soluble Drugs

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 3))

Abstract

The need for novel formulation and process-based techniques to enhance aqueous solubility has increased substantially in recent years. This is primarily due to the limitations of traditional techniques such as physical and chemical stability of the drug substance or the need for toxic solvents that some techniques require. Alternative solubility-enhancement techniques have emerged in recent years to mitigate issues such as these. The purpose of this chapter is to describe emerging technologies for solubility enhancement, allowing the reader to gain an understanding of their utility.

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  1. Pharmaceutics Division, College of Pharmacy, University of Texas at Austin, 1 University Station, A1920, Austin, TX, 78712, USA

    Justin R. Hughey & James W. McGinity

Authors
  1. Justin R. Hughey
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  2. James W. McGinity
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Correspondence to Justin R. Hughey .

Editor information

Editors and Affiliations

  1. , Division of Pharmacy, University of Texas at Austin, Mailstop A1920, Austin, 78712, USA

    Robert O. Williams III

  2. College of Pharmacy, Drug Dynamics Institute, University of Texas, Austin, 78712, Texas, USA

    Alan B. Watts

  3. , Pharmaceutical and Analytical R&D, Hoffmann-La Roche, Inc., Kingsland St 340, Nutley, 07110, USA

    Dave A. Miller

Method Capsule 1

Method Capsule 1

13.1.1 Preparation of Solid Dispersions: KinetiSol® Dispersing

Based on the method reported by DiNunzio et al. (2010b)

Objective

  • To rapidly prepare plasticizer-free solid dispersions containing Eudragit® L100-55

Equipment and Reagents

  • Eudragit® L100-55

  • Itraconazole

  • Liquid nitrogen

  • KinetiSol® Dispersing Compounder

  • Impact mill

  • 60-mesh screen

Method

  • Input an ejection temperature of 158 °C and a rotational speed of 3,000 rpm into the control module.

  • Mix a 1:2 blend of itraconazole:Eudragit® L100-55 in a polyethylene bag for 1-min.

  • Charge the blended material into the processing chamber.

  • Pre-cool steel plates with liquid nitrogen.

  • Start the compounding process.

  • Using the data-acquisition system, monitor temperature and rotational speeds.

  • After material is discharged, quench between chilled plates.

  • Grind the brittle material in an impact mill and pass through a 60-mesh screen.

Results

  • The temperature of the blend reached 158°C in 14.1 s with exposure to temperatures greater than 100°C for only 2 s, resulting in no chemical degradation of Eudragit® L100-55.

  • X-ray powder diffraction patterns indicated that the composition was amorphous.

  • Differential scanning calorimetry thermograms showed the presence of a single-phase system with no endothermic events.

  • The plasticizer-free composition exhibited a high degree of physical stability due to its high glass transition temperature.

13.1.2 Method Capsule 2Preparation of Solid Dispersions: Electrostatic Spinning

Based on the method reported by Verreck et al. (2003a)

Objective

  • To prepare solid dispersions of itraconazole by electrostatic spinning

Equipment and Reagents

  • Hypromellose

  • Itraconazole

  • Ethanol

  • Methylene chloride

  • Electrostatic spinner

  • Turbula mixer

  • Cryogenic mill

  • Liquid nitrogen

Method

  • Prepare physical blends containing 20% w/w or 40% w/w itraconazole by ­mixing in a Turbula mixer for 10 min

  • Prepare a 12% w/w solution of the itraconazole:hypromellose blend in a mixture of ethanol and methylene chloride (40:60 ethanol:methylene chloride w/w)

  • Place the solution into the spinneret and apply a high voltage (16–24 kV)

  • Optional: Mill the resulting fibers by cryogenic grinding

Results

  • SEM analysis demonstrated that drug concentration and processing voltage can significantly impact fiber size and shape.

  • Differential scanning calorimetry thermograms showed that compositions ­containing 20% (w/w) and 40% (w/w) itraconazole were amorphous.

  • Differential scanning calorimetry thermograms indicated that the milling ­process facilitated recrystallization of amorphous itraconazole.

  • Dissolution rates of itraconazole were found to be highly dependent on the drug:polymer ratio, fiber diameter, and presentation used (nonwoven fabrics, milling, etc.).

13.1.3 Method Capsule 3Preparation of Solid Dispersions: Ultrasonic-Assisted Compaction

Based on the method reported by Fini et al. (2002b)

Objective

  • To prepare dispersions of indomethacin by ultrasonic-assisted compaction

Equipment and Reagents

  • Indomethacin

  • Polyethylene glycol 4000, 5500, or 6000

  • Magnesium stearate

  • Talc

  • Ultrasonic-assisted tabletting machine

  • Turbula mixer

Method

  • Mix composition containing 10% indomethacin, 88% polyethylene glycol (4000–6000), 1% magnesium stearate, and 1% talc (w/w) in a Turbula mixer for 15 min.

  • Transfer 1 g of the blend to the ultrasonic-assisted tableting machine equipped with a 25-mm punch.

  • Subject the blend to a frequency of 25 kHz, allowing the polyethylene glycol to become molten.

  • Mill the solidified wafer and sieve such that a particle size range of 75–150 μm is obtained.

Results

  • Differential scanning calorimetry thermograms did not exhibit an endothermic peak associated with indomethacin.

  • X-ray diffractograms of the sonicated composition showed significantly decreased crystallinity in comparison to material that was not sonicated.

  • The dissolution rate of indomethacin was significantly enhanced by ultrasonic compaction.

  • Dissolution rates of indomethacin were found to be highly dependent on energy input with higher levels approaching that of a true solid dispersion.

13.1.4 Method Capsule 4Preparation of Solid Dispersions: Ultrasonic-Assisted Congealing

Based on the method reported by Cavallari et al. (2005)

Objective

  • To prepare multiparticulate dispersions of diclofenac by ultrasonic-assisted compaction

Equipment and Reagents

  • Diclofenac

  • Gelucire 50/13

  • Ultrasonic-assisted congealing apparatus

  • Heat source

Method

  • Heat Gelucire 50/13 to 10°C above its melting point.

  • Add diclofenace (10% w/w) to the Gelucire 50/13 and stir to complete dissolution.

  • Transfer the molten mixture to the thermostated reservoir preset to 60°C.

  • Atomize the molten mass into small droplets by bringing the mass into contact with the sonotrode.

  • Allow the atomized small droplets to fall freely and solidify at room temperature.

  • Collect the microparticles and store in a vacuum desiccator at room temperature.

Results

  • Scanning electron microscopy showed that microparticles were spherical or elliptical in shape and nonaggregated.

  • Sieve analysis demonstrated that the predominant size range was 150–350 μm.

  • Differential scanning calorimetry thermograms did not exhibit an endothermic peak associated with diclofenac at loadings up to 20% (w/w).

  • X-ray diffraction diffractograms exhibited a small degree of crystallinity that can be attributed to diclofenac, indicating that the microparticles were not completely amorphous.

  • Dissolution rates of diclofenac from microparticles were significantly enhanced in comparison to that of the physical mixture.

13.1.5 Method Capsule 5Preparation of Solid Dispersions: Polymeric Micelles

Based on the method reported by Lee et al. (2006)

Objective

  • To prepare polymeric micelles containing paclitaxel suitable for oral administration

Equipment and Reagents

  • Paclitaxel

  • PEG-b-P(VBODENA) copolymer

  • Acetonitrile, DMF, or DMAc

  • Dialysis membrane with 1,000-Da molecular weight cutoff

Method

  • Dissolve 10 mg of block copolymer in 2 mL of acetonitrile, DMF, or DMAc

  • Add paclitaxel to the block copolymer solution at paclitaxel:copolymer ratios ranging from 0.25:1 to 0.6:1

  • Stir the solution for 6 hours at room temperature

  • Dialyze using a membrane against 6 L of distilled water for 24 h

  • Filter through 0.45 μm membrane filters

  • Lyophilize the filtered material containing micelles

Results

  • Loading analysis demonstrated that paclitaxel loading capacity was enhanced with increasing block length of P(VBODENA).

  • Lyophilized micelles could be dissolved in water to achieve a concentration that is five orders of magnitude greater than that of paclitaxel in water.

  • Differential scanning calorimetry thermograms of lyophilized micelles did not exhibit an endothermic event related to paclitaxel, indicating a molecular dispersion.

  • Dynamic light-scattering experiments showed that micelles were between about 105 and 120 nm which was maintained in solution for more than 4 weeks.

  • Cytotoxicity analysis demonstrated that paclitaxel micelles were as much as two orders of magnitude more effective than controls.

  • Bioavailability of paclitaxel was determined to be approximately twofold higher than that of the marketed formulation, Taxol®.

13.1.6 Method Capsule 6Preparation of Solid Dispersions: Mesoporous Silica

Based on the method reported by Mellaerts et al. (2008b)

Objective

  • To prepare mesoporous silica loaded with itraconazole

Equipment and Reagents

  • Itraconazole

  • Ordered mesoporous silica (OMS)

  • Methylene chloride

  • Rotary mixer

Method

  • Prepare a 5 mg/mL solution of itraconazole in methylene chloride.

  • Add OMS at a OMS:Itraconazole ratio of 75:25 and agitate for 24 h with a rotary mixer.

  • Remove methylene chloride by evaporation and dry powder overnight at 35°C.

  • Heat mixture to 100°C for 5 min under vacuum and at 40°C for 48 h to ensure complete removal of methylene chloride.

Results

  • Differential scanning calorimetry thermograms did not exhibit glass transition or endothermic events, indicating that itraconazole was molecularly ­dispersed within the OMS.

  • BET analysis showed that the surface area of OMS decreased from 844 to 355 m2/g after loading with itraconazole.

  • Dissolution studies demonstrated that release rates of itraconazole from OMS were significantly faster than crystalline itraconazole.

  • Bioavailability of itraconazole-loaded OMS was found to be similar to that of the marketed product, Sporanox®.

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© 2012 American Association of Pharmaceutical Scientists

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Hughey, J.R., McGinity, J.W. (2012). Emerging Technologies to Increase the Bioavailability of Poorly Water-Soluble Drugs. In: Williams III, R., Watts, A., Miller, D. (eds) Formulating Poorly Water Soluble Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 3. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1144-4_13

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