Silicate scaffolds with 2-50 nm pores (mesopores) provide support for the amorphous state of drugs and drug-like compounds. The amorphous state in these mesopores is thermodynamically stable against recrystallization. In fact, it has been observed that crystalline drug loads itself into silicate mesopores by vapor phase transfer. Mesoporous silicates are being used by at least two pharmaceutical companies to improve drug exposure in tox studies and as a formulation in Phase I studies.

1. Mesoporous Phases as Supports
for Amorphous Material
Robin H. Bogner, Ph.D.
Professor
Pharmaceutics
Webinar 2017-01-10

2. Amorphous State
• Provides a concentration of drug higher than its equilibrium
solubility  achieve higher oral absorption
• Thermodynamically unstable  recrystallization
UNLESS
1. The drug is molecularly dispersed in a carrier in which its
solubility > drug loading in that carrier.
Marsac PJ, Shamblin SL, & Taylor LS, Theoretical and practical approaches for
prediction of drug-polymer miscibility and solubility. Pharm Res, 2006. 23(10): 2417-26.
2. The drug is incorporated in the pores of a mesoporous
carrier.
Qian KK, Suib SL, & Bogner, RH, Spontaneous crystalline-to-amorphous phase
transformation of organic or medicinal compounds in the presence of porous media, part
2: amorphization capacity and mechanisms of interaction. J Pharm Sci, 2011. 100(11):
4674-86.

3. Mesoporous ≡ 2-50 nm diam. pores
Material Pore Diam.
(nm)
SSA (m2/g) Pore Vol. (mL/g)
Neusilin‡ US2 12 297 1.2
Sorbent‡‡ 62700 4.8 533 0.84
Sorbent 63700 9.1 226 0.81
Sorbent 64700 16 145 0.79
Sorbent 65700 19 124 0.80
Sorbent 66700 31 85.7 0.76
Silysia‡‡‡ 470 12 300 1.2
Silysia 350 21 285 1.7
‡Mg Al Silicate, Fuji Chemical Company, Toyama, Japan and Fuji Health, Burlington, NJ
‡ ‡ Spherical Silica Gel Premium RF, Sorbent Technologies, Norcross, GA
‡ ‡ ‡ ‡ Silica Gel, Fuji Silysia Chemical, Kasugai, Japan and Greenville, NC

4. Spontaneous
Amorphization
Mesoporous silica is amorphous by PLM (a)
Silica:naphthalene 2:1 (w:w) was sealed in
a vial (b)
In less than 2 weeks the crystalline
naphthalene disappeared (c)
Assay of the silica showed that naphthalene
was still present.
4

5. • Polarized Light Microscopy
– Very sensitive, but not quantitative
• Powder X-Ray Diffraction
– May not be able to distinguish between crystallites in the nano-sized pores
and truly amorphous material in the pores
– Amorphous silicates scatter incoming x-rays
• Differential scanning calorimetry
– Often, no discernable Tg, due in part to poor thermal contact of silicates
– Melting point
Jackson & McKenna (1990) The melting behavior of organic materials confined
in porous solids, The Journal of Chemical Physics, 93:9002-9011.
Characterization of the Amorphous
State in Mesoporous Silicates
() cis-decalin, () trans-
decalin, () cyclohexane,
() benzene, ()
chlorobenzene, ()
naphthalene, () heptane

6. Spontaneity
Implies Thermodynamic Stability
Previously suggested to be vapor phase
transfer (Konno 1986)
Some suggested surface diffusion could
not be ruled out since particles were in
contact.
Set the silica and naphthalene in
separate containers in a desiccator.
Assayed samples of the silica for
naphthalene.
Konno T, Kinuno K, and Kataoka K, Physical and Chemical Changes of Medicinals in Mixtures with
Adsorbents in the Solid State. I. Effect of Vapor Pressure of the Medicinals on Changes in Crystalline
Properties. Chem Pharm Bull, 1986. 34(1): 301-307.

7. Equilibrium Amorphization Capacity
Naphthalene with Silica 62700
Qian KK & Bogner RH, Spontaneous crystalline-to-amorphous phase transformation of organic or
medicinal compounds in the presence of porous media, part 1: thermodynamics of spontaneous
amorphization. J Pharm Sci, 2011. 100(7): 2801-15.
7

8. Effect of Pore Size on
Amorphization Capacity
8
4.8 nm
9.1 nm
16 nm
19 nm
31 nm

9. Adsorption 
Capillary Condenstation
9
Once amorphization process is completed,
smallest pores would be completely filled, and
larger pores partially filled with drug molecules
• Reduction in pore volume
• Mean pore diameter can be smaller, larger, or remain the same,
depending on the thickness of adsorbed layer

10. Ibuprofen in Mesoporous Silicate
10
For a 3-g formulation (2-g SiO2 and 1-g ibuprofen):
• Pore volume loss in SiO2 = 2g x (0.85 cm3/g – 0.12 cm3/g) = 1.46 cm3
• Volume occupied by ibuprofen (ρ = 0.92 g/cm3): 1.09 cm3

11. Amorphization Capacity
Mean pore
diameter
(nm)
SSA
(m2/g)
Naphthalene
at capacity
(mg/g of SiO2)
4.8 534 530
9.1 226 81
16 145 42
19 124 32
31 86 22
11

12. Amorphization Capacity
Mean pore
diameter
(nm)
SSA
(m2/g)
Naphthalene
at capacity
(mg/g of SiO2)
Area-normalized
capacity
(mg/m2 of SiO2)
4.8 534 530 0.98
9.1 226 81 0.36
16 145 42 0.29
19 124 32 0.26
31 86 22 0.26
12

13. Amorphization Capacity
Mean pore
diameter
(nm)
SSA
(m2/g)
Naphthalene
at capacity
(mg/g of SiO2)
Area-normalized
capacity
(mg/m2 of SiO2)
4.8 534 530 0.98
9.1 226 81 0.36
16 145 42 0.29
19 124 32 0.26
31 86 22 0.26
12 300 150 0.50
21 285 73 0.26
Fuji Silysia
13

14. Amorphization Capacity
Mean pore
diameter
(nm)
SSA
(m2/g)
Naphthalene
at capacity
(mg/g of SiO2)
Area-normalized
capacity
(mg/m2 of SiO2)
4.8 534 530 0.98
9.1 226 81 0.36
16 145 42 0.29
19 124 32 0.26
31 86 22 0.26
12 300 150 0.50
21 285 73 0.26
12 297 208 0.70
Fuji Silysia
Neusilin US2 14

15. Why does naphthalene have an
affinity for a silica surface?
Wouldn’t a hydrophobic surface provide a better scaffold for naphthalene?
Silysia 350 pore size 21 nm
Sylophobic 200 pore size 19 nm
Hydrophobic surface
reduces capacity.
Jackson CL & McKenna GB, The melting behavior of organic materials confined in porous solids. Journal of Chemical Physics, 1990. 93(12): 9002-9011.
Pan X, Julian T, & Augsburger L, Increasing the Dissolution Rate of a Low-Solubility Drug Through a Crystalline-Amorphous Transition: A Case Study with
Indomethicin. Drug Development and Industrial Pharmacy, 2008. 34(2): 221-231.
Qian KK, Suib SL & Bogner RH, Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous
media, part 2: amorphization capacity and mechanisms of interaction. J Pharm Sci, 2011. 100(11): 4674-86.

16. Competition for the silica surface
by water
• Nothing competes for a silica surface like water does.
• Good news and bad news
• Bad news -- must keep amorphous drug supported by silica VERY DRY
• Good news – dissolution should be almost instantaneous

17. Naphthalene dissolution is enhanced
3:1 Silica:Napthalene in 900 mL water at 37 °C

18. Limitations – Silicates
• Silicates are effective catalysts for oxidation reactions.
• Silicate surfaces are acidic.
Silicate
Suspension‡
pH pHeq
‡‡
Neusilin FL2 9.6 8.8
Neusilin US2 8.8 7.1 – 7.5
Aerosil R812S 3.5 2.3
Aerosil 200 4.2 2.2
‡4% suspensions
‡‡pHeq measured by diffuse reflectance of pH indicators
Low pH
High pH
Amorphous quinapril hydrochloride
degradation was consistent with low
surface pH of silicates.
Hailu SA & Bogner RH, Effect of the pH grade of silicates on chemical stability of coground amorphous quinapril
hydrochloride and its stabilization using pH-modifiers. J Pharm Sci, 2009. 98(9): 3358-72.

19. Enhanced Bioavailability: TAS-301 melt-
adsorbed onto porous calcium silicate
• TAS-301 solubility 20 ng/mL
• Florite RE (Eisai) SSA 128 m2/g
• Drug:Silicate 1:2 melt-adsorbed
– Confirmed amorphous by DSC & XRD
– TAS-301 concentration 600 ng/mL
– Bioavailability in beagles
Kinoshita M, et al., Improvement of solubility and oral bioavailability of a poorly water-soluble drug,
TAS-301, by its melt-adsorption on a porous calcium silicate. J Pharm Sci, 2002. 91(2): 362-370.
Encapsulated Formulation Fed/Fasted AUC0-24 h Enhancement
Crystalline drug
Fasted
4.6
3.7
Melt-adsorbed drug 16.9
Crystalline drug Standard
diet
9.4
3.0
Melt-adsorbed drug 27.8

20. Bioavailability of a poorly-soluble
weak base
• Itraconazole – solubility ~1 ng/mL, pKa 3.7
• SBA-15 – pore diameter 7.3 nm, SSA 862 m2/g
• Drug:silicate 1:4 – solvent deposited in methylene chloride
Van Speybroeck M, et al., Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral
absorption of the poorly soluble weak base itraconazole. Eur J Pharm Biopharm, 2010. 75(3): 354-65.

21. Improved wetting by silicate
also aids enhancement
Silicates are easily wetted by water.
Density 2.2 g/mL
Solvent-deposit ITR (30%) onto/into Neuslin US2  good wetting
Solvent-deposit ITR (40%) onto/into Neuslin US2  good wetting
At 50%, the surface of Neusilin US2 is dominated by ITR
Grobelny P, Kazakevich I, Zhang D, Bogner R, (2015) Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison
of excipients and processing methods, Pharmaceutical Development and Technology, 20(1): 118-127.

22. Processing can alter wetting
• Co-milling collapses pores  reduces amorphization capacity
• More drug is on the surface  reducing wetting
Grobelny P, Kazakevich I, Zhang D, Bogner R, (2015) Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison
of excipients and processing methods, Pharmaceutical Development and Technology, 20(1): 118-127.
Lu Y. Tang N, Lian R, Qi J, Wu W, Understanding the relationship between wettability and dissolution of solid dispersion. International
Journal of Pharmaceutics, 2014. 465(1–2): 25-31.

23. Conclusion
• Mesoporous silicates provide scaffold to thermodynamically
stabilize amorphous drug  supersaturated concentrations
• Pore size < 15 nm  higher capacity for amorphization
• Limitations
– water displaces drug  storage at low relative humidity
– acid-labile and oxidation-labile drugs
• Bioavailability enhanced in at least one report (TAS-301: Florite)
• Mechanisms of enhancement
– Amorphous  supersaturated solution
– Water displaces drug  rapid dissolution
– Below amorphization capacity  silicate improves wetting

24. Yin-Chao Tseng
Manish Gupta
Deepak Bahl
Shumet Hailu
Ken Qian
Pawel Grobelny
Arushi Manchanda
Irina Kazakevich
Dina Zhang
Bayer
Kildsig Center for
Pharmaceutical
Processing Research
American Foundation for
Pharmaceutical
Education
Merck
Acknowledgements