From lab scale to industrial scale (industrial scale is the American model)

As everyone in R&D knows, pharmaceutical process scalability can be challenging and stressful. I have been there myself: my purification was dreadful, and I was almost hoping in secret that the project would fail to avoid the ramp-up process. But what if there was a way to take the stress out of scaling-up since we just can’t only work at the lab scale? Now that I know better, I am sharing how to excel at scaling-up purifications and eliminate the concerns of having large scales results mirroring those from the lab bench.

The first steps are always the same: 1) screen test bulk SiliaMetS and SiliaCarb. Then 2) optimize the purification at the lab scale with the bulk Scavenger.

Now step 3 is where most people that excel at transferring from lab to pilot/commercial know a trick. Instead of transferring the information from step 2 directly for a larger set-up, apply the results to a lab-scale SiliaMetS and SiliaCarb E-PAK flow cartridge which can then be linearly scaled-up with ease to treat several hundred kilograms of solution.

We already highlighted the E-PAK’s scalability for metal catalyst removal in drug development here and here. Today, let’s look at how easy it can be.

From Laboratory to Industrial Production

On a bigger scale, the kinetics and thermodynamics of the reaction need to be re-evaluated to find the right parameters. This makes scaling-up a multistep synthesis a challenge in the development of active pharmaceutical molecules (API), with purification steps being a substantial part of it.

To remove precious metal catalysts, reaction by-products, or colors from your synthetic reaction mixtures or natural products, the radial flow adsorption cartridges of E-PAK proved their efficiency with eliminating undesired products such as palladium, nickel, ruthenium, rhodium, iridium, copper, and even organic impurities, just to name a few.

Different sorbents accommodate different purposes with metal Scavenger SiliaMetS cartridges, bare silica SiliaFlash cartridges, and activated carbon SiliaCarb cartridges. Consequently, the first step is always to screen sorbents. More than one could be used at the same time as Scavengers are synergistic.

Sorbents for E-PAK
Active AdsorbentsFor Removal and/or Recovery of :pH Operation
SiliaMetS Thiol (1.2 mmol/g)Pd, Ag, Hg, Os, Ru, Cu, Ir, Pb, Rh, Se & Sn2 to 9
SiliaMetS DMT (0.5 mmol/g)Pd, As, Ir, Ni, Os, Pt, Rh, Ru, Se, Cd, Co, Cu, Fe, Sc & Zn
SiliaMetS AMPA (0.8 mmol/g)Al, Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Mn, Nd, Ni, Pm, Pr, Sb, Sn, Tb, Tm, V, Yb, Co, Cu, Fe, Mg & Zn
SiliaMetS Imidazole (0.96 mmol/g)Cd, Co, Cu, Fe, Ir, Li, Mg, Ni, Os, W, Zn, Cr, Pd & Rh
SiliaBond Amine (1.2 mmol/g)Pd, Cr, Pt, W, Zn, Cd, Co, Cu, Fe, Hg, Ni, Pb, Ru, Sc & Se
SiliaMetS Diamine (1.28 mmol/g)
SiliaMetS Triamine (1.11 mmol/g)
SiliaMetS TAAcOH (0.41 mmol/g)Ca, Co, Ir, Li, Mg, Ni, Os, Ru, Sc, Cr, Cs, Fe, Pd, Rh & Sn
SiliaMetS TAAcONa (0.41 mmol/g)Ca, Cd, Cs, Cu, Fe, Ir, La, Li, Mg, Ni, Os, Rh, Sc, Sn, Cr, Pd, Ru, Se & Zn
SiliaBond Cyano & Florisil (1.38 mmol/g)Various organic molecules
SiliaBond Propylsulfonic Acid SCX-2 (0.63 mmol/g)Amines & Anilines, Ion Exchange
SiliaFlash Bare SilicaVery vast range of organic impurities, metals, pigments...
SiliaCarb CA (Chemically Activated Carbon)Precious metal catalysts, pigments and reaction contaminants1 to 13
SiliaCarb VA (Vegetable Activated Carbon)
SiliaCarb VW (Virgin Wood Carbon)
SiliaCarb HA (Highly Active Carbon)

With the lab-scale housing, parameters such as the number of equivalents of sorbent required (molar equivalent method or weight/weight method), flow rate, scavenging time, number of recirculations, and solvent are screened to bring scavenging to the desired level. Then, the purification technology allows you to go seamlessly from a few grams to kilograms of sorbent, purifying up to 10,000 L at once, with total linear scalability. With the multiple round housing, up to 12 cartridges can run in parallel.

See the multiple round housings (European model) next to a person for scale. These can hold 3, 7 or 12 E-PAK cartridges simultaneously.

When Scavenger to impurity ratio, residence time, temperature, solvent, contaminant, and compound levels are constant, linear extrapolation of adsorbent mass has proven to be quite accurate. All you need are the scale-up factors that you can find in Table 2.

Table 2. Scale-Up Calculations for Silica-Based Adsorbents
Cartridge Sizes5 x 1 cm5 x 10 cm5 x 25 cm16.5 x 12.5 cm16.5 c 25 cm16.5 x 50 cm16.5 x 100 cm
Scale-up Factor-102580220440875
Mass of Silica (g)8752008751,7503,5007,000
Bed Volume (cm3)18.81884702,3754,7509,50019,000
Recommended Flow Rate (mL/min)7.5751909501,9003,8007,600
Flow Rate Range (mL/min)1 – 2010 – 20025 – 500100 – 2,500250 – 5,000500 – 10,0001,000 – 20,000
Conditioning (mL)1506001,3507,50015,00035,00070,000

When scaling up your reaction, the level of impurities might not stay constant. To keep the Scavenger to impurity ratio constant, you might need to evaluate the impurity ratio of your scaled-up reaction and adjust the quantity of Scavenger accordingly. You should also adjust the flow rate to keep residence time consistent.

To do so, once you have optimized your lab-scale purification, including flow rate, use the bed volume (in cm3 or mL) and the optimized flow rate (in mL/min) of the lab-scale purification to establish optimal residence time (in min). You can then find your new flow rate using the large scale’s bed volume.

Bed volume lab scale (cm3 or mL)  = residence time (min⁡)
Flow rate lab scale (mL/min)

Bed volume large scale (cm3 or mL)  = flow rate large scale (mL/min)
residence time (min⁡)

For example, if you use a 5 x 1 cm cartridge, with a bed volume of 18.8 mL at a flow rate of 7.5 mL/min, your residence time is 18.8 mL / 7.5 mL/min = 2 min 30 seconds. To keep this same residence time with the 16.5 x 100 cm cartridge with a bed volume of 19,000 mL, your flow rate must be 19,000 mL / 2.5 min = 7,600 mL/min.

Now let’s look at the scale-up step in action with two different reactions: a Sonogashira and a Suzuki-Miyaura coupling reaction.

Scaling Up a Sonogashira Purification

For the coupling of aryl halides with terminal alkynes, a Sonogashira coupling is a realistic example to showcase the efficiency of the E-PAK purification scale-up with regards to Pd and Cu removal.

After a successful Sonogashira coupling, purification conditions were screened and optimized, and we used SiliaMetS E-PAK cartridges to purify the crude product. We studied recoveries and back pressure on the scale-up of the reaction clean-up. Looking at the metal scavenging step with SiliaCarb followed by SiliaMetS for Pd removal resulted in the following (Tables 3 and 4) in which we observe that API recovery (%) stayed constant and backpressure stayed minimal while increasing cartridge sizes.

Table 3. SiliaCarb VW results for lab to pilot scale purifications
SiliaCarb VWE-PAK Flow (ml/min)Max Pressure (psi) API Recovery (%)Final Pd Concentration (mg/kg)Scavenging Yield (%)
1 x 5 cm10 0 856991
10 x 5 cm75 0 896991
25 x 5 cm190 9 856192
12.5 x 16.5 cm1,000 5 856192

Table 4. SiliaMetS DMT results for lab to pilot scale purifications
SiliaMetS DMTE-PAK Flow (mL/min)Max Pressure (psi)API Recovery (%)Final Pd Concentration (mg/kg)Scavenging Yield (%)
1 x 5 cm80911298
10 x 5 cm750915> 99
25 x 5 cm19019951298
12.5 x 16.5 cm1,0003904> 99

Going from gram to kilogram scale can thus be done confidently and proportionally while respecting the amount of sorbent used and residence time. Comparable scavenging yields were obtained while recovery and backpressure remained constant (Table 3 and 4) regardless of the cartridge’s size when using the scaling factor in Table 2 to transpose the purification while keeping solvent (Ethyl Acetate), temperature (22°C), and time (4 h) constant.

Scaling Up a Suzuki-Miyaura Purification

This time for a Suzuki-Miyaura reaction and a purification of Pd, the scavenging efficiency by the number of recirculation cycles (up to 7 cycles) was plotted to better compare the scavenging kinetics using cartridges of different sizes up to the largest commercial format available (16.5 x 100 cm). Once again, the parameters such as solvent, reaction time, and temperature were held constant with the others adjusted based on the pre-determined factors from Table 2. The plot below demonstrates the ease and linearity of using flow cartridges. Regardless of size, the same trend is observed: the first cycle yielded 90 % scavenging while the remaining cycles incrementally captured Pd up to 98 %.

Steps to Scaling Up

In both cases, the Suzuki-Miyaura and the Sonogashira clean-ups, the same steps were pursued. An initial Scavenger screening and optimization were followed by purification with the E-PAK SiliaCarb and SiliaMetS cartridges using the same parameters (type and amount of Scavenger, time, solvent, and temperature) using the series pass technique (i.e. two E-PAK cartridges were connected in series).

Using the scale-up factor from Table 2, adapting the cartridge size and the flow rate, we transposed the purification to a larger E-PAK scale with a bigger housing and bigger cartridges.

In addition to eliminating the need to filter and to manipulate dust, one of the major interests to the E-PAK is its linear scalability, with simple multiplication factors to fit the new scale needed. If you wish to be part of those who excel at scaling up their purification too, E-PAK technology has everything you are looking for. Other pharmaceutical companies are already doing it to simplify metal content removal, so what are you waiting for?

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Eliane, M.Sc

Eliane is the Scientific Content Specialist here at SiliCycle, with years of experience both in the lab and client support. She studied at Laval University, for both her Bachelor’s and Master’s in Chemistry. In fact, her thesis was in organic electronics in which purity is of the utmost essence, making her in-tune to the purification needs of chemists.