Nanocrystal technology for drug formulation and delivery
Tzu-Lan CHANG1,Honglei ZHAN1,Danni LIANG2,Jun F. LIANG1,*()
1. Department of Chemistry, Chemical Biology, and Biomedical Engineering, Charles V. Schaefer School of Engineering and Sciences, Stevens Institute of Technology, Hoboken, NJ 07030, USA
2. Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
With the development of modern technology like high throughput screening, combinatorial chemistry and computer aid drug design, the drug discovery process has been dramatically accelerated. However, new drug candidates often exhibit poor aqueous or even organic medium solubility. Additionally, many of them may have low dissolution velocity and low oral bioavailability. Nanocrystal formulation sheds new light on advanced drug development. Due to small (nano- or micro- meters) sizes, the increased surface-volume ratio leads to dramatically enhanced drug dissolution velocity and saturation solubility. The simplicity in preparation and the potential for various administration routes allow drug nanocrystals to be a novel drug delivery system for specific diseases (i.e. cancer). In addition to the comprehensive review of different technologies and methods in drug nanocrystal preparation, suspension, and stabilization, we will also compare nano- and micro-sized drug crystals in pharmaceutical applications and discuss current nanocrystal drugs on the market and their limitations.
. [J]. Frontiers of Chemical Science and Engineering, 2015, 9(1): 1-14.
Tzu-Lan CHANG, Honglei ZHAN, Danni LIANG, Jun F. LIANG. Nanocrystal technology for drug formulation and delivery. Front. Chem. Sci. Eng., 2015, 9(1): 1-14.
Drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions; ease of scale-up and little batch-to-batch variation; narrow size distribution of the final nano-sized product; flexibility in handling the drug quantity, ranging from 1 to 400 mg·mL?1; low energy technique
Residues from milling media; slow process; unstable
150–400 nm
High-pressure homogenization (HPH)
Allow aseptic production of nanosuspensions for parenteral administration; universally applicable; easy down-stream processing; fast method; possibility for aqueous-free production; (the others are the same as the WBM)
Prerequisite of micronized drug particles; prerequisite of suspension formation using high-speed mixers before subjecting it to homogenization; technique consumes high energy; requires experience in operation
40–500 nm
Tab.1
Techniques
Advantages
Disadvantages
Size ranges
Hydrosol
It can produce crystalline drug nanoparticles
The drug has to be soluble in at least one solvent; the process involves organic solvents that need to be removed
100–400 nm
Nanomorph?
The amorphous form has higher saturation solubility and a faster dissolution rate than the crystalline form
Undesired compound recrystallize to the crystalline state and the bioavailability was decreased subsequently
5–5000 nm
Sonoprecipitation
Simple setup; significant reduction in the use of organic solvents
More suitable for production of amorphous nanoparticles; immersion depth of horn tip must be established experimentally; slow production time
80–130 nm
High gravity controlled precipitation(HGCP)
Can produce crystalline particles; suspensions can be recycled for prolonged mixing and reaction; it has been scaled-up for commercial manufacturing; no need to use a stabilizer
Equipment is highly specialized and not widely available
200–500 nm
Evaporative precipitation techniques
Cost effective; easy to operate; can be easily scaled for massive production
May not be suitable for heat-labile compounds
4–2600 nm
Rapid expansion of supercritical solution (RESS)
Uniform size distribution; less processing steps
Low solubility of polar drugs in sc-CO2; agglomeration of the small particles
45–500 nm
Supercritical anti-solvent (SAS)
This process can take place at near ambient temperatures; small particle size; easy scale-up
The presence of residual toxic solvents in the final product
45–500 nm
Spray freezing into liquid (SFL)
Highly porous amorphous and smaller size nanocrystals in the form of solid solution are produced; improve dissolution rates and bioavailability of poorly water soluble APIs
The drug should have a low glass transition temperature (Tg)
~7000 nm
Tab.2
Techniques
Advantages
Disadvantages
Size ranges
Nanoedge?
Improved particle size reduction effectiveness
Residues of organic solvents in the nanosuspension, especially in large-scale production; the particle sizes are much bigger than the standard technologies; the process is often complicated and expensive
177-930 nm
H69
The top-down step reduces the particle size as well as stabilizes the nanocrystals with the applied energy; the annealing step promotes the more stable crystalline form
The resulting nanosuspensions contain organic solvent residues.
22-921 nm
H42
Relatively short processing times during SD; solvent-free dry intermediates; small drug nanocrystals after a reduced number of HPH cycles
The high temperatures applied during the SD could make this technology unsuitable to process thermolabile compounds
172-636 nm
H96
The low temperatures and the high yields of the FD make it suitable to process thermolabile or expensive drugs; the FD step eliminates the organic solvent content and make the nanosuspensions ready to be processed or used
The extension of the FD step
62-440 nm
CT (Combinative Technology)
The reduction of the homogenization pressure and process length; the improved physical stability of the nanosuspensions
The particle sizes are relatively bigger than the other combinative processes
275-604 nm
Tab.3
Stabilizing system (%w/w to compound)
Compound (%w/v in suspension )
Production method
Category
Cremophor? EL (100%)
1,3-Dicyclohexyl urea (1%)
MM
Surfactant
Tyloxapol (50%)
Budenoside (1%)
HPH
Surfactant
Lecithin (20%/40%/167%)
RMKP 22 (3%)
HPH
Surfactant
Sodium lauryl sulfate (5%)
Spironolactone (10%)
HPH
Surfactant
Poloxamer 338 (50%)
Camtothecin (2%)
MM
Surfactant
Acacia gum (2%)
ucb-35440-3 (5%)
HPH
Polymers
Polyvinyl alcohol (30-70 kDa; 50%)
Beclomethasonedipropionate (5%)
MM
Polymers
HPC (60 kDa; 2.4%/4.8%/9.6%/19.3%)
Undisclosed (16%)
MM
Polymers
Povidone K15 (30%)
Danazol (5%)
MM
Polymers
Lecithin (50%)-tyloxapol (20%)
Budenoside (1%)
HPH
Surfactant combination
Poloxamer 188 (100%)-lecithin (50%)
Buparvaquone (1%)
HPH
Surfactant combination
Poloxamer 18-sodium deoxycholic acid
Itraconazole
HPH
Surfactant combination
Tween? 80 (20%)-lecithin (10%)
Azithromycin (1%)
HPH
Surfactant combination
Tween? 80 (16.7%)-Span 80 (33.3%)
Piposulfan (2%)
MM
Surfactant combination
Carbopol 974 P (2.5%)-Tween? 80 (12.5%)
Albendazole (4%)
HPH
Polymer-surfactant combination
HPC-sodium lauryl sulfate
Cilostazol
MM
Polymer-surfactant combination
HPC (80%)-sodium lauryl sulfate (1.6%)
MK-0869 (5%)
MM
Polymer-surfactant combination
HPMC (K4MCR; 12.5%)-Tween? 80 (12.5%)
Albendazole (4%)
HPH
Polymer-surfactant combination
Polyvinyl alcohol (50%)-poloxamer 188 (50%)
Buparvaquone (1%)
HPH
Polymer-surfactant combination
Tab.4
Fig.3
Fig.4
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