Irina Kazakevich, PhD

Merck & Co., Inc.

AAPS 2014

San Diego

November 6, 2014

Porous Inorganic Excipients as Carriers for Amorphous Solid Dispersions

• Introduction

– How are insoluble molecules formulated?

• Current Formulation Approaches

– Enabled formulations overview

• Innovative Alternatives to Existing Formulation Platforms:

– Porous inorganic excipients as carriers

– Case studies

• Summary

• Acknowledgments

Outline

2

Introduction

3

580

122

174

200

191

340

76

0 100 200 300 400 500 600 700

PRACTICALLY INSOLUBLE

VERY SLIGHTLY SOLUBLE

SLIGHTLY SOLUBLE

SPARINGLY SOLUBLE

SOLUBLE

FREELY SOLUBLE

VERY SOLUBLE

Solubility of Marketed Products

Impact: • Inability to achieve target exposure in safety studies

• Low exposure and variable PK in clinical studies

• Greater potential for food effect and PPI effect

• High pill burden for patients

Source: www.pharmacircle.com

Formulation Approaches to Overcome Dissolution-Limited Absorption of BCS II/IV Compounds

4

•Noyes-Whitney Equation:

𝒅𝑴

𝒅𝒕= 𝑫𝑺(𝑪𝒔 − 𝑪)/𝒉

where:

D-diffusion coefficient

S-surface area of exposed solid

h-the thickness of the diffusion layer

Cs- solubility of the solute

C-concentration of the solute in bulk solution at

time t

Source: C.McKelvey et al., Harvard Advanced Materials Pharmaceutical Symposium, Nov.28-30, 2011

S↑ Cs↑ S↑

Cs↑

Dissolution-Limited Absorption: How to Improve Dissolution Rate

Alternative Carriers For Solid Dispersions

Organic Polymers Inorganic Porous Excipients:

TO PRODUCE STABLE AMORPHOUS DISPERSION

WE CURRENTLY USE

Well developed.

Many commercial

products

Research area, no

commercial products

available yet

• Silicon Dioxide • Magnesium Alumosilicate

• Anhydrous Calcium

Phosphate

• Calcium Carbonate

Silica has multiple forms and applications

6

History of Silica Used in Drug Delivery

1977

• Rupprecht et al., first reported the use of silica beads as a drug carrier. Codeine was utilized as a model drug and the silica gel beads had pores in the size of 1-5 micron suitable for sustained release

1992

• MCM-41 ( Mobile Composition of Matter, No.41), first synthesized ordered amorphous silica gel

• 2-5 nm pore size; spec. surface area ~1000 m2/g for particle size

1996

• SBA-15 (Santa Barbara Amorphous) – developed at University of California, Santa Barbara, ordered amorphous silica gel:

• 8-11 nm pore size; spec. surface area ~600 m2/g; particle size: 1-2 um

Early 2000’s

• Mesoporous silicates first looked at for delivery of poorly water soluble API’s, and after that…

Source: S.Kucera, Parteck SLC, Merck KGaA, An Innovative Solution for

Bioavailability Enhancement, June 5, 2014

Not all silicon dioxides are the same

Commercially available silica for pharmaceutical applications: Syloid ( 244, 72, and AL1) FP Silica, from W.R.Grace &Co,-Conn.

Aeroperl, Sipernat, and Aerosil, from Evonik

Parteck SLC 500&800, from EMD Millipore

Neusilin US2, Fuji Chemical Industry Co., LTD.

Source: Syloid FP Customer Presentation, Grace, 2012

Porous

Excipient

Description Morphology PSD*, µm Source

D10 D50 D90

Parteck

SLC 500

Silica gel

5.8 18.8 38 EMD Millipore

Neusilin US2 Granulated

magnesium

aluminosilicate

82 204 392 Fuji Chemical

Aeroperl 300 Granulated

fumed silica

6.5 43.6 111.2 Evonik

Syloid 244FP Silica gel

131 259 352 Grace

General Characteristics of Commercially Available Porous Silica-Based Excipients

9

* - PSD data were generated internally at Merck by Sympatec HELOS Particle size Analysis, except Parteck SLC 500

Nitrogen Adsorption Isotherm as a Powerful Tool to Characterize the Surface Properties of Porous Excipients

𝑃𝑃0

𝑎 1 − 𝑃𝑃0

=1

𝑛𝑚𝐶+

𝐶 − 1

𝑛𝑚𝐶𝑃𝑃0

S = 16.4 [Å2] . nm

𝐶 ≅ 𝑘1𝑒𝑥𝑝𝐻𝑎 − 𝐿

𝑅𝑇

•From S.J.Gregg, K.S.W.Sing, Adsorption, Surface Area and Porosity, AP 1982, London

Porous structure •Cylinders; corpuscular, slit-type slit flakes

a – adsorption

P/P0 – relative pressure

nm – monolayer capacity Ha – Heat of adsorption

L – Heat of N2 condensation

Approximate ranges of C-constant: 10 – 30 – hydrophobic surface

40 – 70 – aromatic, or polarizable

80 and higher – polar

100 – 150 – typical silica

BET

equation

Nitrogen adsorption

data

Surface

Area

C (BET)

constant

Pore

volume

Pore diameter

max. average

m2/g mL/g Å Å

Parteck SLC500 366 81 0.73 66 60

Neusilin US2 397 136 1.37 88 120

Aeroperl 300 235 110 1.67 270 370

Syloid 244FP 271 128 1.52 166 176

Material Surface Chemistry Characterization by Nitrogen Adsorption/Desorption Isotherms

11

0

2

4

6

8

10

12

0 200 400 600 800

Pore

Siz

e D

istr

ibution

Pore diameter, (Å)

Parteck SLC500

Neusilin US2

Aeroperl 300

Syloid 244FP

0

10

20

30

40

50

0 0.2 0.4 0.6 0.8 1

Adsorp

tion,

mm

ol/g

Relative Pressure, P/Po

Parteck SLC500

Neusilin US2

Aeroperl 300

Syloid 244FP Material Characteristics from Nitrogen

Adsorption/Desorption Isotherms:

• Porous morphology differs significantly for all studied

excipients.

• All excipients demonstrate comparable high surface

area.

• Surface Energy (C-constant), calculated from BET

equation, reflects highly hydroxylated silica surface

Inorganic porous excipient based amorphous solid dispersions can be produced via co-milling (solid-solid), wet impregnation/melt adsorption (liquid-solid) , spontaneous amorphization ( vapor-solid).

Commercial scale-up information is not available, however, many lab and pilot-plant batches were manufactured by:

• Fluid Bed Impregnation (Plamen Grigorov et al., Rutgers)

• Spontaneous evaporation and sublimation ( Ken Qian et al.)

• Spray Drying (Abhijit Gokhale, Patheon, and Dina Zhang, Merck)

• Hot-Melt Extrusion ( Jenifer Maclean at al., Amgen)

• Co-Milling ( Dr. Robin Bogner, UConn, and multiple groups within Merck)

• Wet Impregnation/Solvent Deposition ( Michiel van Speybroeck et al. Formac., Sean Kucera at al., EMD Millipore; and many others)

How to Load Crystalline Drug Substance onto Porous Excipients to Produce Amorphous Solid Dispersion?

• Problem Statement: CNS drug has significantly decreased bioavailability when co-

administered with proton pump inhibitors.

• Goal: Develop PPI resistant formulation

• Formulation Screening Results: (i) Conventional formulation has shown a

significant PPI effect; ( ii) Enabled formulations such as nano, SP and HME, have demonstrated low POS due to the intrinstic properties of the molecule such as pH-dependent solubility, high melting point, low solubility in SD solvents at ambient temperature, and low solubility in LFC solubilizing vehicles.

• Alternative Formulation Approach: Co-milling with Neusilin US2 to produce

amorphous solid dispersion.

Case Study: Improving Bioperformance of CNS Drug by Co-Milling with Neusilin US2

13

0

20

40

60

80

100

120

140

0 2 4 6

So

lub

ilit

y, m

g/m

L

pH

Aqueous Solubility of MK-XX Form Crystalline Free Base

pKa 5.7

Melting point 256°C

Tg 74°C

Log P 2.3

Aqueous Solubility (µg/mL)

SGF: 162.5;

FaSSIF: 1.96; FeSSIF: 5.95

BCS II

• Experimental Design:

• Bioperformance:

• Physical stability: up to 1 month at 40C/75%RH, up to 1 year at ambient conditions

• Conclusion: PPI-resistant formulation was developed for PK Safety studies in dogs at lab scale (50 g). No line of sight to commercialization due to the absence of commercially available pharmaceutical milling equipment.

Case Study: Improving Bioperformance of CNS Drug by Co-Milling with Neusilin US2

14

Blending MK-A, Neusilin US2, Excipient

Co-Milling Encapsulation

Formulation AUC0-8

(µM*hr)

Cmax (µM)

Conventional tablet (famotidine) 0.0135

±0.00148

0.00667±0.00

228

Conventional tablet predissolved in

SGF (famotidine)

0.314 ± 0.0273 0.152 ±

0.0183

Neusilin based dry blend capsule

(famotidine)

0.303 ± 0.168 0.0985 ±

0.0426

Case Study: Itraconazole/Parteck SLC 500 Amorphous Dispersion by Wet Impregnation

Source.: Sean Kucera, Parteck® SLC – An Innovative Solution for Bioavailability Enhancement, Merck KGaA

How Processing Route and the Nature of Solid Carrier Affect the Properties of Amorphous Solid Dispersions. Merck/UConn Scientific Collaboration.

• Model compound: Itraconazole (ITR)

Description

Neusilin US2 Mesoporous amorphous magnesium aluminosilicate

Veegum-F Non-porous magnesium aluminosilicate

A-TAB Macro porous crystalline anhydrous calcium phosphate

Solvent Deposition (SD) Co- Milling (CM)

• Composition: ITR/Excipient

• Processes:

Melting Point 178°C

Solubility: 0.1N HCl

water

4-6 µg/mL

1-4 ng/mL

pKa, weak base 3.7

BCS Class II

Surface Properties of Itraconazole Amorphous Dispersions and Corresponding Excipients

17

NEUSILIN

SD

milled

Excipient Loading Capacity by Solvent Deposition of Itraconazole

18

Loading capacity [%]

50 > 10 > 6

Neusilin US2 > A-TAB > Veegum F

PXRD patterns of ITR, Neusilin US2, Veegum F and A-TAB and ITR solvent-deposited in/on the three excipients at loading levels above and below the apparent amorphization capacity are shown below:

ATR-FTIR scans of crystalline and amorphous ITR, and ITR solvent-deposited using Neusilin US2, A-TAB, and Veegum F along with scans of the neat excipients.

Note:

Neat amorphous ITR shows band broadening, but no other significant differences from the crystalline form.

No spectral shifts are observed suggesting the presence of hydrogen bonding between the drug and excipients.

Amorphization Rate of Itraconazole by Co-Milling with Excipients of Different Nature

19

Amorphization time (or time to disrupt the crystalline state) by co-milling at a single level of ITR (30%) are in the order of :

ITR:Neusilin US2 < ITR:A-TAB < ITR:Veegum F < ITR crystalline

Effect of Milling on Surface Properties and Loading Capacity of Neusilin US2

•Nitrogen adsorption isotherms of Neusilin

original (blue), Neusilin milled for 30 min (red),

and Neusilin milled for 60 min (green).

•PXRD patterns of (a) crystalline ITR and 30% ITR solvent-

deposited on Neusilin US2 where the Neusilin was (b)

unmilled or previously milled for (c) 30 min or (d) 60 min.

a

b

c

d

•SSA, m2/g of milled Neusilin by BET:

•397 > 152 > 57 •As is > 30 min > 60 min

Milling affects significantly the

porosity of the material, decreases the

surface area of Neusilin US2 and,

subsequently, its loading capacity.

Dissolution profiles of crystalline ITR and ITR deposited on/into excipient. ITR crystalline (black squares); ITR melt-quneched (black circles); 6% ITR:Veegum (red); 10% ITR:ATAB (blue); 30% ITR:Neusilin US2 (green).

Dissolution Enhancement of Itraconazole

21

Dissolution profiles of a crystalline ITR and 30% ITR

co-milled with excipient. ITR crystalline (black

squares); neat ITR milled 3 hours (black circles);

30% ITR:Veegum (red); 30% ITR:ATAB (blue); 30%

ITR:Neusilin US2 (green).

Dissolution conditions: USP Type 2 Apparatus, SGF pH 1.2 at 37°C, 500 mL, 250 rpm, 30 mg ITR

Physical Stability of Itraconazole Amorphous Dispersions

22

Stability at 40°C/0% RH of the dissolutioneof Itraconazole by Neusilin at 3 Loading

Levels using (a) co-milling or (b) solvent-deposition for amorphization

Formulation

Storage time [month] Initial/0 2 3

Concentration (μg/mL)

Neat ball milled Itraconazole 19.1

14.1

15.0

Neat melt quenched Itraconazole 36.0

39.3

38.5

Bal

l mil

led

30% Itraconazole : Neusilin US2 30.0

29.9

30.6

40% Itraconazole : Neusilin US2 25.7

26.1

30.3

50% Itraconazole : Neusilin US2 24.9

24.8

24.6

Solv

ent

dep

osi

tio

n 30% Itraconazole : Neusilin US2

40.3

42.0

41.3

40% Itraconazole : Neusilin US2 39.9

39.4

40.9

50% Itraconazole : Neusilin US2 34.1

36.6

38.0

Physical Stability of Itraconazole Amorphous Dispersion at 50%DL by XRPD

23

XRPD of 50% ITR solvent-deposited on Neusilin US2 and stored at 40 °C/0%RH

and 40 °C/75%RH for 2 months.

• Dry milling is a very attractive “green” approach which allows to remove the solvent from the process to produce amorphous solid dispersion. However, it is a very complex process where the excipient plays a part in the transfer of mechanical energy to the drug, creates mechanical barriers and, in some cases, intermolecular bonds to prevent drug’s recrystallization in solid state and serves as stabilizer of amorphous form upon dissolution. Among three evaluated excipients Neusilin US2 has demonstrated superior amorphization potential and stabilization of amorphous form in solid dispersions produced by milling.

• Wet impregnation loading approach is widely used for producing amorphous solid dispersions on lab scale. The unique characteristics of porous excipients such as high surface area and large pore volume provide significant benefits in drug loading capacity and stabilization of amorphous form by confinement in narrow pores. With wet impregnation it was possible to achieve 50% ITR DL on Neusilin US2, compare to 10% on A-TAB, and 6% on Veegum F, non-porous excipients.

Merck/UConn Collaboration Summary

24

• Numerous research groups in academia and the pharmaceutical Industry are working on innovative applications of porous excipients to produce stable amorphous dispersions via multiple processing routes.

• Advantages of using porous excipients as alternative carriers for solid amorphous dispersions include well defined pharmaceutical safety profile, commercial availability, enhanced dissolution profile, good flowability, and compactibility of final blend.

• The mechanism of amorphization and stabilization of porous inorganic carrier-based amorphous solid dispersions is depend upon the loading process and interfacial interactions between an adsorbed drug and the surface of the porous carrier. A complete understanding of surface chemistry is required prior to the use of porous carriers for producing amorphous dispersions.

Conclusions

25

• Merck Research Laboratories:

– Dina Zhang, PhD

– Louis Crocker, PhD

– John Higgins, PhD

– David Dubost, PhD

– Steven Wang, PhD

– Anthony Leone, PhD

• Michiel Van Speybroeck, PhD, Formac Pharmaceuticals

• Ken Qian, PhD, NIST

• Janine Sink, Grace

• Michael Greene, Mutchler

Acknowledgments

26

• University of Connecticut:

– Dr. Robin Bogner and her research group

• EMD Millipore:

– Sean Kucera, PhD

– Thomas Brennan

Thank You!

27