SiriusT3For compound screening anddetailed PhysChem characterization

Use it for

Early stage compound screening

· In synthetic chemistry, measuring pKahelps in selecting the best structures fordevelopment

· Good compound selection reduces the riskof costly late stage failures

· Up to 80 pKa samples a day; automationreduces operator time

PhysChem characterization

· Understand the ionization state of a drug,how it varies with pH and its effect onabsorption

· Learn how the pKa changes due to solventinteractions, partitioning, precipitation orbinding

· Improve ADME predictions and evaluatehow changes to the molecule can affectthe log P for a desired application.

Pre-formulation

· Preparing detailed PhysChem profiles

· Learn about the molecule’s capacity forsupersaturation and LLPS formation

· Assess dissolution rates using very smallsample weights

Importance of pKaMost small-molecule drugs ionize in aqueous solutions.Ionization occurs when the molecules acquire or lose hydrogenions in response to changes in the pH. When pH goes up (e.g. inthe GI Tract), bases convert from ionized to neutral andbecome more lipophilic and less soluble. These changes affectthe rate of absorption. pKa values affect many otherproperties, too. Chemists often improve drug candidates bymaking substitutions to change their pKa.

ScreeningSiriusT3 is ideal for high throughout pKa measurement insupport of drug discovery. In most labs, 80% of samples willsucceed first time by a Fast UV/cosolvent method. Failures canbe re-measured by pH-metric, or flagged for future attention ifthe compound gets through DMPK.

SiriusT3 measures pKa, log P, log D and solubility of

ionizable drugs and small molecules, requiring minimal

amounts of sample. It also measures dissolution of

ionizable and neutral compounds in volumes down to 1.5

mL. SiriusT3 instruments are used in labs that support

drug discovery, crop science research, by universities,

biochem and CROs.

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Spectral data vs. pH for sample with two pKas

Five miniature probesentering sample vial

Measuring pKaIf a molecule has a pKa between 2 and 12, SiriusT3 will find it.Many drugs absorb UV, and the intensity vs. wavelengthchanges when they ionize. Our UV-metric methods determinepKa values from these changes. Around 80% of drug pKavalues can be successfully measured in about 15 minutes byour Fast UV method, which requires only 5 µL of 10 mM stocksolution (typically 10 µg). Those pKas that are not associatedwith UV change can be measured by our pH-metric method,which requires less than 1 mg of solid sample.

Prediction and measurementScientists often use software to predict pKa values. It’spowerful and fast, but it doesn’t always get things right. Thisgraph shows measured vs. predicted pKa for 115 pKasmeasured in our Applications Laboratory in 2013. We’reconfident in the measured values, but it would be risky tobase development strategies on some of the predictions.

log P, solubility and microscaledissolution – find out moreSirius pH-metric methods for measuring log P and solubilityof ionizable compounds are supported by several validationstudies. And for chemists who don’t have enough sample forUSP-style dissolution experiments, SiriusT3 can be used fordissolution of small sample weights in small volumes.Methods are described on our website, along with recordingsof webinars about pKa, log P, solubility and dissolution.

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192 sample positions seen from above

What customers say“SiriusT3 integrates perfectly in our analytical workflow”.

“It is a good fit, filled the gap we had in the company”.

“…a pre-requisite for DMPK studies”.

“It has become a part of our screening cascade to aid in selection ofcompounds to move forward into further PK testing”.

“The SiriusT3 is an integral part of a pool of instruments for physicochemicalcompound characterization. For pKa and log P/D measurements, SiriusT3 isthe Golden Standard”.

Sirius AnalyticalRiverside, Unit 12, Forest Row Business Park, Forest Row, East Sussex, RH18 5DW, UK

Telephone: +44 (0) 1342 820720Fax: +44 (0) 1342 820725Email: sirius@sirius-analytical.comweb: www.sirius-analytical.com

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SIRIUST3 TECHNICAL SPECIFICATION

pH electrode Ag/AgCI, double junction reference

pH range 1.8 - 12.2, standardized by Sirius Four-Plus™

Electrodestorage

Home position for electrode storage, pH7 buffer positions for calibration

Stirrer Overhead, variable speed, computer controlled

TemperatureMeasured by thermocouple at every datapoint.Controlled by Peltier, range 12 °C to 70 °C

Turbiditydetection

Pass-through light detection – percentage light detectedreported to 0.1%

Reagents Water, Acid, Base, partition solvent, CoSolvent

Partitionsolvents

Supports 7 including Octanol, Dodecane, Toluene

CoSolventsSupports 10 including Methanol, Acetonitrile, DMSO andDioxane. Six can be installed, via automated valve.

DispensersPrecision dispensers, 0.5 mL syringes, multi-tip capillarybundle, minimum volume of 0.024 μL

Probemovement

Fully automated X-Y axis on titrator module

Washes Wash station provides static and flowing washes

AutoloaderHolds up to 192 samples, automatic robotic gripper arm for transfer to sample position

Purge gas Two internal flow meters, nitrogen or argon supply required

Assay volume 1.0 to 3.5 mLs

Environment

For indoor use onlyAltitude ≤2000 mTemp. 5 °C to 40 °CMax relative humidity 80% @ 31 °CMains voltage fluctuation +/- 10%Installation overvoltage Cat IIPollution degree 2

SIRIUST3 ASSAY SPECIFICATION

Analytical methodsTemplates supplied for all supported assays.Users can save customized templates if required.1-2-3 template for setting up cosolvent pKa assays.

pKa

Determine pKa values to the highest commercially availableaccuracy• Results in 15 minutes by Fast UV for most samples• UV-metric method for extended pKa range of 0.5 to 13.5 • pH-metric assays for samples without pH/UV activity• Cosolvent methods for poorly soluble samples• Yasuda-Shedlovsky plots for cosolvent pKas • Generate distribution of species plots• Determine buffer capacityStandard assay conditions: 0.15 M KCl, 25 or 37 °C.Sample requirement: UV, 10 μg; pH-metric, 1 mg

log P

• Determine log P and log D vs. pH• Study octanol/water & many other mixtures• Built-in methods for high, medium and low log P• No need for time-consuming shake-flask style experiments

in multiple pH buffers.• Sample requirement: 1 - 2 mg

Solubility

• Determine intrinsic solubility and kinetic solubility• Derive pH vs. solubility profile• Determine supersaturation• Sample requirement: 1 - 10 mg, depends on solubility

Dissolution Microscale methods to profile drugs for dissolution andprecipitation rates• Explore the effects of changing pH

Assay Expert

Optional integrated software prediction module (powered by ACD) to analyse structure and identify ionizable groups,identify whether they are acidic or basic and estimate pKaand log P values. Predicted properties are used toautomatically optimize the design of experiments.

Reagents• Minimal running costs - uses off the shelf reagents with

no special “kits” required.

Getting samples todissolve

• Built in ultra-sonic bath to aid measurements of insolublecompounds.

Automated acid and base pre-dose can be programmed.

Clean-up assays

Short automated procedures for cleaning electrode and probes.Low to high and high to low pH with cosolvent present;surfactant wash at end.

PHYSICAL DIMENSIONS WEIGHT HEIGHT WIDTH DEPTH

Dispenser module 35 kg/77.16 lbs 700 mm 260 mm 460 mm

Titrator 23 kg/50.71 lbs 490 mm 215 mm 460 mm

Autoloader 27 kg/59.52 lbs 490 mm 350 mm 460 mm

Total 85 kg/187.39 lbs 700 mm 825 mm 460 mm