an r&d service performed for a mid-sized pharmaceutical

CASE STUDY

An R&D service performed for a mid-sized pharmaceutical company

Two-Step Purification with E-PAK® Cartridges Following a Direct Pd-Catalyzed BorylationUnpublished raw data

CHALLENGE & PROJECT SCOPE

Optimization of a Palladium purification protocol, following a borylation reaction, using E-PAK® cartridges. Comparison with traditional purification techniques.Pd(OAc)2 Phase III CompoundInitial Concentration: 4,280 ppmTarget: < 20 ppm

HIGHLIGHTED BENEFITS & ADVANTAGES

Standard Process:• 1st filtration on activated carbon followed by washings• 2nd washing of the obtained organic phase with conc.

HCl to achieve an effective phase separation• 2nd filtration on activated carbon followed by washings• Treatment with 30% w/w SiliaMetS Thiol for 6 h at 60°C• 3rd filtration, followed by evaporation• Recrystallisation from cold Heptane

E-PAK Optimized Process:• 1st E-PAK Treatment: SiliaCarb HA (2-3 Passes)

• 2nd E-PAK Treatment: Si-DMT (7-8 Passes)

All at RT

CASE STUDY: Purification of a Borylation Reaction using E-PAK® Technology

PROJECT

This work was sponsored by a mid-sized pharmaceutical company that is a SiliCycle customer since 2014. The API involved herein is in Phase III trials.

In this project, after evaluating various & more traditional purification means, they opted for SiliCycle’s SiliaMetS Metal Scavengers for the efficient removal of Palladium which was contaminating a synthetic intermediate following a direct Pd-catalyzed borylation reaction.

SiliCycle was able to successfully optimize the entire purification protocol through its new integrated solution: E-PAK® radial-flow cartridges, a product specifically developed for pharmaceutical purifications from R&D scale to full production. Advantages of this technology include full recovery of API, marginal leaching, solvent & extended pH range compatibility, straightforward scalability, environment friendly, sound economics. The details of this optimization are described below.

As part of a large scale manufacturing process, the purification of a direct Pd-catalyzed borylation step was initially performed via two successive treatments: a two-pass filtration through activated carbon (using twice the same carbon filtration cartridge), followed by a Palladium scavenging step with SiliaMetS Thiol.

I

OB

O** O **B

O

+

1. Pd(OAc)2 (0.029 equiv.) Ph3P (0.040 equiv.)

Cs2CO3 (1.5 equiv.)MeOH

2.

1st Purification through

Activated Carbon filtration

EtOAcHClaq

1. SiliaMetS Thiol 30 % w/wEtOAC

50°C, 5 - 6 h

3. solvent swap, crystallization

2. filtration

Intermediate SRecovery : 95 %Pd content : under 20 ppm(1.2 equiv.)

OB

O**

Dark brown in colorPd content : around 1,000 ppm

OB

O**(1.0 equiv.)

2nd Purification throughsame Activated Carbon pad

Process Scale: 50 - 100 kg. Optimization experiments have been done on 200 g.

Experimental procedure • In a 5 L three-neck-flask was introduced 1,93 L of methanol (HPLC grade), Pd(OAc)2 (21.38 mmol), PPh3 (29.50 mmol) and Cs2CO3

(1,105 mmol).The reactor was purged with argon, while maintaining mechanical agitation. The iodobenzene compound (737.2 mmol) and the chiral diboron (884.7 mmol) were then added, while maintaining a slight argon stream.

• The mixture was stirred under inert atmosphere for 3 hours at 50°C, (starting iodide was totally consumed). Methanol was evaporated until approximately 1000 mL was left. A portion of 2,000 mL of ethyl acetate was added, and the organic phase washed with 1,100 mL of HClaq (4M).

• The obtained mixture was then used as is, to test different purification procedures / sorbents.

Albeit good recovery (95 %) and satisfying Palladium removal (< 20 ppm) obtained on a process scale of 50 - 100 Kg, one main issue was highlighted:

• The activated carbon filtration step showed to be inefficient, requiring high amount of Metal Scavenger in subsequent purification step, and thus increasing processing time. Improving the effectiveness of this step was required.

This one point was addressed as part of the optimization of this purification process on a 200 g scale.


FIRST, ROUGH PURIFICATION: ACTIVATED CARBON FILTRATION

Preliminary tests in standard filtration conditionsOut of the four available activated carbons in E-PAK Cartridges, three were tested in a standard filtration procedure following the borylation reaction.

Pd Scavenging Following Carbons Filtration (Initial [Pd]: 4,280 mg/kg)

Filtration Purification Conditions Pd Concentration (mg/kg) Scavenging (%)

SiliaCarb CA Filtration - 1st passage 866 80

SiliaCarb CA Filtration - 2nd passage 785 82

SiliaCarb HA Filtration - 1st passage 739 83

SiliaCarb HA Filtration - 2nd passage 640 85

SiliaCarb VW Filtration - 1st passage 935 78

SiliaCarb VW Filtration - 2nd passage 704 84

Experimental procedure • Following the borylation reaction work-up, 3 x 60 mL of the organic phase were filtered through 0.56 g of three different activated

carbon (SiliaCarb CA, SiliaCarb HA and SiliaCarb VW) and rinsed with 12 mL of ethyl acetate.

• A 0.5 mL sample of each filtrate was collected, and analyzed by ICP-OES for Pd content.

• Each filtrate was washed again with 70 mL of aqueous HCl (4 M), and filtered through the same carbon filter cakes.

• A 0.5 mL sample of each filtrate was collected, and analyzed by ICP-OES for Pd content.

Conclusions• Although all three carbons gave similar results, SiliaCarb HA showed slightly better scavenging performance.

• In all cases, the 2nd treatment improved the scavenging results to some extent.

• Hence, activated carbon SiliaCarb HA was selected for the subsequent tests with E-PAK cartridges.

Optimized purification through SiliaCarb HA Carbon E-PAK CartridgesA 5 x 1 cm SiliaCarb HA (5 g) E-PAK cartridge was inserted in the appropriate housing (lab scale housing).

Pd Scavenging with a 5 x 1 cm (lab scale) SiliaCarb HA E-PAK Cartridge (Initial [Pd]: 4,280 mg/kg)

E-PAK Purification Conditions Pd Concentration (mg/kg) Scavenging (%)

SiliaCarb HA Filtration - 1st passage 655 85

SiliaCarb HA Filtration - 2nd passage 510 88

SiliaCarb HA Filtration - 3th passage 539 87

Experimental procedure • 150 mL of ethyl acetate (HPLC grade) was first used to pre-condition the unit.

• 525 mL of the crude solution was then passed through the cartridge at a 12.5 mL/min flow rate.

• Lastly, the cartridge was eluted three times at the same flow.

• At each passage, a 0.5 mL sample was collected and analyzed by ICP-OES for Pd content.

ConclusionTwo consecutive passes through a 5 x 1 cm SiliaCarb HA E-PAK cartridge was shown to be sufficient to obviate a second HCl washing step and yield decreased Pd content.


SECOND, MORE TARGETED PURIFICATION: SILIAMETS METAL SCAVENGING

Preliminary tests in bulk conditionsScavenging screenings are the best way to start off with SiliaMetS functionalized resins. This is because even for the same functionality or metal, a variation in the scavenging efficiency can be observed depending on the nature of the products present in the solution to be treated. For example, steric hindrance, electronic effects, H-bond, all are factors that can greatly influence the scavenging %.

In order to determine the most suitable Pd scavengers for the current system, a screening was realized using 8 of our most suitable grafted silicas. Influence of temperature and reaction time were evaluated at the same time.

Pd Scavenging Screening for 1 h at r.t. (Initial [Pd]: 1,150 mg/kg)

SiliaMetS 10 % w/w (%) 20 % w/w (%) 30 % w/w (%)

SiliaMetS Cysteine 47 64 71

SiliaMetS Diamine 38 59 68

SiliaMetS DMT 67 91 97

SiliaMetS Imidazole 67 85 91

SiliaMetS TAAcOH 35 53 60

SiliaMetS Thiol 44 54 63

SiliaMetS Thiourea 68 93 97

SiliaMetS Triamine 21 33 40

Pd Scavenging Screening for 1 h at 50°C (Initial [Pd]: 1,150 mg/kg)










Pd Scavenging Screening for 4 h at r.t. (Initial [Pd]: 1,150 mg/kg)











Pd Scavenging Screening for 4 h at 50°C (Initial [Pd]: 1,150 mg/kg)










Experimental procedure • A 500 mL solution of 50 g of Intermediate S in ethyl acetate (HPLC grade) was made in a volumetric flask.

• In respect to Intermediate S: samples of 80 mg (10 % w/w), 160 mg (20 % w/w) and 240 mg (30 % w/w) of 8 different SiliaMetS were pre-weighed in 24 polypropylene tubes suited for SiliCycle’s MiniBlock® Platform.

• 8 mL of the above solution (containing 0.8 g of Intermediate S) was added to each tube.

• The MiniBlock Platform was orbitally shaken for 60 min. at room temperature, and sample of 0.5 mL of each solution were collected and filtered through 0.45 µm filters.

• The remaining solutions were shaken for 3 more hours and filtered off.

• All obtained samples (48) were analyzed by ICP-OES for Pd content.

• An identical manipulation was made at 50°C, generating 48 more samples to be analyzed.

Conclusions• SiliaMetS DMT and SiliaMetS Thiourea were shown to be the best scavengers for efficient Pd removal from this process stream.

• 20 to 30 % w/w of grafted silica was necessary to obtain satisfactory Pd scavenging.

• Increasing temperature and reaction time slightly improved scavenging performances.


Leaching investigationIn order to determine if any extractables had leached into the final product, the following experimentation was run.

Experimental procedure • Samples of 0.3 g of SiliaMetS DMT was suspended into 5 mL of ethyl acetate (HPLC grade), and shaken for 4 hours at room temperature.

• The suspension was filtered through a 0.45 µm syringe filter, evaporated and reconstituted in 1 mL of methanol (HPLC grade).

• A blank sample was also assayed.

• LC-MS (ESI+) was run on both samples. No extractables were detected by LC/MS/MS.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1961 120 180 240 299 359 419 479 538 598 658 717 777 837 896 956 1016 1076 1135

0.0

2.0e7

4.0e7

6.0e7

8.0e7

1.0e8

1.2e8

1.4e8

1.6e8

1.8e8

2.0e8

2.2e8

2.4e8

2.6e8

2.8e8

2.9e8

Inte

nsity

, cps

Time, min

Reagent blank

SiliaMetS DMT in ethyl acetate

Optimized purification through SiliaMetS DMT E-PAK CartridgesFollowing previous results, E-PAK purification was conducted under 20 and 30 % w/w conditions.

Pd Scavenging Following Each Elution (Initial [Pd]: 1,103 mg/kg)

SiliaMetS 20 % w/w Pd Concentration (mg/kg) 20 % w/w Scavenging (%) 30 % w/w Pd Concentration (mg/kg) 30 % w/w Scavenging (%)

1st elution 333 70 304 74

2nd elution 243 78 248 78

3th elution 180 84 173 85

4th elution N/A N/A 132 89




Experimental procedure• A 5 x 1 cm SiliaMetS DMT (8 g) E-PAK cartridge was inserted in the appropriate housing

(laboratory scale).

• 150 mL of ethyl acetate (HPLC grade) was first used to pre-condition the unit.

• Solution S was prepared adding 40 g of Intermediate S to 200 mL of ethyl acetate in a volumetric flask. A 0.5 mL sample was retrieved for subsequent ICP-OES analysis.

• The entire solution was passed through the cartridge at a 12.5 mL/min flow rate.

• Lastly, the cartridge was eluted three times at the same flow.

• Samples of 0.5 mL were collected after each run, and analyzed by ICP-OES for Pd content.


A similar experiment was run following a 30 % w/w ratio (acc. to preconditionned E-PAK SiliaMetS DMT).

• Hence, 133 mL (26.6 g of Intermediate S) of Solution S was passed through a new E-PAK SiliaMetS DMT at 12.5 mL/min flow.

• Lastly, the cartridge was eluted 7 times at the same flow.

• Samples of 0.5 mL were collected after each passage, and analyzed by ICP-OES for Pd content.

Conclusions20% w/w was sufficient to achieve maximal scavenging of Pd.

Side reaction investigationFinal products obtained above were analyzed by LC-MS (ESI-), along with a sample of intermediate S. Methanol (HPLC grade) as a blank sample was also tested.

ConclusionNo new product was detected.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1961 120 180 240 299 359 419 479 538 598 658 717 777 837 896 956 1016 1076 1135

Time, min

0.0

5.0e6

1.0e7

1.5e7

2.0e7

2.5e7

3.0e7

3.5e7

4.0e7

4.5e7

5.0e7

5.5e7

6.0e7

6.5e7

6.9e7

Inte

nsity

, cps

Methanol (HPLC grade) Intermediate S E-PAK SiliaMetS DMT elution (20 % w/w) E-PAK SiliaMetS DMT elution (30 % w/w)

Final Conclusions

• All tedious & time consuming steps of the initial traditional purification protocol could be avoided:

1. 1st filtration on activated carbon followed by washings with fresh ethyl acetate

2. 2nd washing of the obtained organic phase with HClaq (4 M)

3. 2nd filtration on activated carbon followed by washings with fresh ethyl acetate

4. Treatment with 30 % w/w of SiliaMetS Thiol at 60oC for 6 h

5. 3th filtration, followed by ethyl acetate evaporation

6. Recrystallisation from cold heptane

• Activated carbon SiliaCarb HA provided the best scavenging results among all three tested carbons.

• Two consecutive passes through an E-PAK SiliaCarb HA cartridge obviated a second HCl wash.

• Treatment of the Intermediate S with 20 – 30 % w/w of SiliaMetS DMT in bulk mode at room temperature provides a good way to get rid of over 98 % of Pd.

• Similar results were obtained when the compound was filtered through an E-PAK SiliaMetS DMT cartridge (20 – 30 % w/w of SiliaMetS DMT) at room temperature, but from an experimental point of view, the modus operandi with E-PAK cartridges may be considered as a much more user friendly procedure and great alternative to avoid the presence of insolubles in reactor.

SiliCycle can help you design, scale up & optimize metal removal processes. Contact us at [email protected]


E-PAK Cartridges PortfolioLab ScaleLab scale cartridges are designed to facilitate the evaluations of small samples. Testing with loose media can be done with samples as small as a few milliliters and are normally done in advance of cartridge testing to identify the formula offering the best results.

Lab Scale Cartridges

Cartridge Size Diameter x Height Flow Rate Range Pressure Drop ∆P (Psig)

with w/1 cps Fluid

Media Weight

SiliaMetS & SiliaBond SiliaFlash & Activated Carbons

5 x 1 cm 1 - 20 mL/min ≤ 5 psig 8 g 5 g

5 x 10 cm 10 - 200 mL/min ≤ 5 psig 75 g 50 g

5 x 25 cm 25 - 500 mL/min ≤ 5 psig 200 g 125 g

Pilot & Commercial ScaleE-PAK pilot scale cartridges provide rapid processing for volumes from 10 to hundreds of liters, and can establish the parameters for larger scales, since E-PAK offer linear scalability.

E-PAK commercial scale cartridges provide rapid processing for manufacturing operations needing to process batch sizes of > 10,000 liters or can be adapted for continuous operation.

Pilot & Commercial Scale Cartridges

Cartridge Size Diameter x Height Flow Rate Range Pressure Drop ∆P (Psig)

with w/1 cps Fluid

Media Weight

SiliaMetS & SiliaBond SiliaFlash & Activated Carbons

Pilot Scale

16.5 x 12.5 cm 0.10 - 2.5 L/min ≤ 10 psig 875 g 850 g

16.5 x 25 cm 0.25 - 5 L/min ≤ 10 psig 1.75 kg 1.7 kg

Commercial Scale

16.5 x 50 cm 0.50 - 10 L/min ≤ 10 psig 3.5 kg 3.4 kg

16.5 x 100 cm 1 - 20 L/min ≤ 10 psig 7 kg 6.8 kg

Both Pilot and Commercial cartridges are provided with a Code 8 (closed top & open bottom end caps-bottom with double 2-222 Teflon® encapsulated Viton® o-ring) cartridge sealing configuration.

To meet commercial processing requirements, E-PAK cartridges can be operated in line or in parallel for increased capacity.

STRATEGY FOR FINE-TUNING THE PURIFICATION PROCESS

Combination of an initial, rough purification with activated carbon together with a second metal scavenging protocol is a very powerful purification strategy.

Yet, even with good purification results in hand, the scale-up of these conditions from R&D to process laboratories, all the way to industrial scales remains a huge challenge.

Created with proprietary technology, E-PAK radial flow adsorption cartridges provide rapid adsorption kinetics and processing capacities suitable for all purification scales: laboratory, pilot and commercial operations.


SiliCycle E-PAK cartridges are available packed with three different activated carbons (C941, C947, C948) and six different silicas (SiliaFlash Bare Silica, SiliaMetS Thiol, SiliaMetS DMT and SiliaMetS Amine, Diamine, Triamine).1

Activated carbons and bare silica gels are useful for the removal of various impurities, metallic and organic, as well as pigments, and volatile compounds, whereas functionalized resins are extremely specific to given metals or organics:

SiliCycle’s Scavengers for E-PAK Cartridges

Scavenger Structure Description

Scavenger for:

Typically Scavenges

Met

als

Elec

troph

iles

Nuc

leop

iles

Ioni

c Bo

ndin

g

PGI *

SiliaMetS ThiolPN: R51030B

Loading: ≥ 1.20 mmol/g Endcapping: yes Solvent Compatibility: All

Si SH

SiliaMetS Thiol is our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions.

Ag, Hg, Os, Pd & Ru Cu, Ir, Pb, Rh, Se & Sn

SiliaMetS DMTPN: R79030B


Si NH

N

NN

SH

SH

SiliaMetS DMT is the silica - bound equivalent of 2,4,6 - trimercaptotriazine (trithiocyanuric acid, TMT). It is a versatile metal scavenger for a variety of metals and the preferred metal scavenger for ruthenium catalysts and hindered Pd complexes (i.e. Pd(dppf)Cl2).

As, Ir, Ni, Os, Pd, Pt, Rh, Sc,Ru & Se Cd, Co, Cu, Fe, Sc & Zn

SiliaBond AminePN: R52030B


Si NH2

Also known for their electrophile scavenging efficiencies and their base reagent qualities, SiliaMetS Amine, Diamine and Triamine have proven to be very useful for the scavenging of the following metals: Pd, Pt, Cr, W and Zn.

Cd, Cr, Pd, Pt, Rh & Ru Co, Cu, Fe, Hg, Pb, W & ZnAcid chlorides, Aldehydes, Anhydrides, Chloroformates, Isocyanates, Ketones, Sulfonyl ChloridesAcids & Acidic Phenols

SiliaMetS DiaminePN: R49030B


Si NH

NH2

Cr, Pd, Pt, W & Zn Cd, Co, Cu, Fe, Hg, Ni, Pb, Ru, Se, V & ScAcid chlorides, Aldehydes, Anhydrides, Chloroformates, Isocyanates, Ketones, Sulfonyl ChloridesAcids & Acidic Phenols

SiliaMetS TriaminePN: R48030B


Si NH

NH2

HN

Cr, Pd, Pt, W & Zn Ag, Cd, Co, Cu, Fe, Hg, Ni, Os, Pb, Rh, Ru & Sc

Acid chlorides, Aldehydes, Anhydrides, Chloroformates, Isocyanates, Ketones, Sulfonyl ChloridesAcids & Acidic Phenols

* PGI: Potentially Genotoxic Impurities

1 More SiliaMetS in E-PAK Cartridges to come soon!


Scale-UpOne of the strongest benefits of SiliCycle E-PAK Cartridges is their linearity upon scale-up. As shown below, in a typical Suzuki-Miyaura coupling for which palladium needed to be removed, each format behaved very similarly in terms of efficiency (scavenging %), kinetics and relative capacity.

NH

Br

COOEtNH

COOEt+ +

tBu

B(OH)2

Pd(OAc) 2P(o-tol) 3

HCO3i-PrOH, H

2O

NH

COOEt

tBu

Experimental Conditions

E-PAK Format Bead volume (mL)

Flow rate (mL/min)

Residence Time (min:sec)

5 cm x 1 cm 18.8 10 01:53

5 cm x 12 cm 188 100 01:53

5 cm x 25 cm 470 250 01:53

16.5 cm x 25 cm 4,750 2,600 01:50

16.5 cm x 100 cm 19,000 10,400 01:50

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Sca

veng

ing

Effic

ienc

y (%

)

Number of Recirculation Cycles

5 cm x 1 cm

5 cm x 10 cm

5 cm x 25 cm

16.5 x 25 cm

16.5 x 100 cm

Once the best purifications sorbents have been identified in bulk, transferring the conditions from bulk to cartridges can be a very robust strategy for rapid and efficient scale-up.

Scale-Up CalculationAlthough there are always exceptions, scale-up projections based on a linear extrapolation of adsorbent mass have proven to be quite accurate when test conditions including contact time, temperature, solvent type and contaminant and compound levels are held constant. The following table shows the scale-up/relative change in mass between lab, pilot and commercial size E-PAK cartridges.

Scale-Up calculation for Silica-Based Adsorbents

Cartridge Sizes 5 x 1 cm 5 x 10 cm 5 x 25 cm 16.5 x 12.5 cm 16.5 x 25 cm 16.5 x 50 cm 16.5 x 100 cm

Scale-up Factor - 10 25 80 220 440 875

Mass of Silica (g) 8 75 200 875 1,750 3,500 7,000

# mmol SiliaMetS Thiol (1.20 mmol/g) 9.6 90 240 1,050 2,100 4,200 8,400

# mmol SiliaMetS DMT (0.50 mmol/g) 4.0 38 100 438 875 1,750 3,500

# mmol SiliaMetS Imidazole (0.96 mmol/g) 7.7 72 192 840 1,680 3,360 6,720

# mmol SiliaBond Amine (1.20 mmol/g) 9.6 90 240 1,050 2,100 4,200 8,400

# mmol SiliaMetS Diamine (1.28 mmol/g) 10.2 96 256 1,120 2,240 4,480 8,960

# mmol SiliaMetS Triamine (1.11 mmol/g) 8.9 83 222 971 1,942 3,885 7,770

Bed volume (cm3) 18.8 188 470 2,375 4,750 9,500 19,000

Recommended Flow Rate (mL/min) 7.5 75 190 950 1,900 3,800 7,600

Typical Flow Rate Range (mL/min) 1 - 20 10 - 200 25 - 500 100 - 2,500 250 - 5,000 500 - 10,000 1,000 - 20,000

Approximated Tank Volume 50 mL 200 mL 450 mL 2.5 L 5 L 11.6 L 23.3 L

Conditionning 150 mL 600 mL 1.35 L 7.5 L 15 L 35 L 70 L

* Estimated data

Measurement Methodology:

• Scale-up Factor: mass of silica / 8 g (smallest size)• Mass of Silica (g): upon packing of cartridge• # mmol SiliaMetS XXX (X.X mmol/g): silica mass x typical loading of SiliaMetS / SiliaBond• Bed volume (cm3): cake total volume, excluding cap, including middle hole

• Recommended Flow Rate (mL/min): for residence times of 2.5 minutes• Flow Rate Range (mL/min): for residence times from 1 to 20 minutes• Conditionning: 3 x Tank volume including cartridge

High Value Silica-based and Specialty Products for Chromatography, Analytical and Organic Chemistry, and PurificationC E R T I F I É E I S O 9 0 01 : 2 015 C E R T I F I E D

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an r&d service performed for a mid-sized pharmaceutical

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