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Test Material Adsorption Paresh Masuria

What was the issue? Why does it happen? How does it happen? Influencing factors Filtration effects Remedial action Conclusion

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Page 1: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Test Material Adsorption

Paresh Masuria

Page 2: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Agenda

What was the issue? Why does it happen? How does it happen? Influencing factors Filtration effects Remedial action Conclusion

Page 3: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion
Page 4: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

A Sticky Situation!

Issue Stability study conducted at GSK Low Day 0 analytical results during Phase 1 20% reduction in nominal conc. over time (Days 0 – 7) TM; Compound A Vehicle; Water

Hypothesis Low results possibly due to TM adhesion to scintillation vials Issue experienced during previous stability studies

Page 5: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Why?

Page 6: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Why?

Scintillation vials are made of Borosilicate glass Consists of BoronOxide and Silica More thermo stable & less dense compared to

common glass (prepared from soda lime) They contain Silanol (Si-O-H) functional groups on their surface Susceptible to deprotonation;

During interaction with aqueous solutions (e.g. Water), deprotonation of scintillation vial surface occurs

Removal of H+ proton from Silanol group; SiO-H → SiO- + H+ Produces electro-negative (-) charge on the inner walls of scintillation vial Creates an attractive force for electro-positively (+) charged molecules

i.e. Acidic functional groups present in Compound A Resulting in initiation of adsorption of Compound A

Page 7: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

How?

Page 8: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

How? Adsorption: Adhesion of atoms / ions / molecules from a dissolved solid to a surface In our formulation;

Acidic Carbonyl (C=O) group of Compound A undergoes nucleophilic chemical reaction Nucleophile (Nu-) is the deprotonated scintillation vial surface Chemical bond between (C=O) and (Nu-) Results in hydrolysis of Compound A

Consequently, denaturing the chemical structure of Compound A Reduction of Compound A (active material) within the formulation Verified by low analytical results in stability study

Page 9: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Influencing Factors? pH

Adsorption may affect the formulation pH Measured pH values within stability study: 2.5 – 5.5 (at 10 – 0.01 mg/mL respectively) Results typically on the low side – Indicative of acidic nature of Compound A

Temperature Adsorption becomes more profound when interaction between adsorbant (scintillation vial)

and adsorbate (Compound A) occurs across thermo stable surface Scintillation vials are known to be good at retaining heat (high thermal stability) Provide a perfect medium for this interaction

Concentration Adsorption may occur irrespective of formulation conc. This suggests it is not relative (or progressive) to formulation conc. In most cases, only 1-2% of TM adheres to scintillation vials (across all conc.) However, at lower conc. there is greater possibility of TM to be hydrolysed Due to larger surface area of nucleophilic sites in proportion to acidic molecules within formulation Therefore, adsorption more evident at lower conc. (0.01 mg/mL), compared to higher conc. (10 mg/mL) Consistent with results obtained throughout stability study

Page 10: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Membrane Filters Adsorption may also explain low analytical results obtained from formulation filtration

via membrane filters

Millex-GV PVDF membrane filters used at GSK

Consist of open colloidal structures Hydrophilic Known to cause less adhesion compared to Nylon / PTFE membrane filters Therefore, any TM content reduction may not be attributed to hydrolysis

Page 11: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Van Der Waal’s Force Adsorption observed using PVDF membrane filters may be related to electrostatic interaction between

TM and Filter Opposite electro charges between the TM (+) and Filter (-) attract via Van Der Waal’s forces

VDW Force: Attraction between opposite electro charges in atoms / molecules / surfaces Typically weak bonding However, VDW force of adhesion is dependent upon the surface of interaction Fewer surface asperities (unevenness) result in a larger area of contact between the particles and

surface (i.e. TM + Filter) Consequently increasing the force of attraction Open colloidal structure of PVDF filters provide an ideal medium for VDW interaction

Page 12: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Remedial Action

Page 13: What was the issue?  Why does it happen?  How does it happen?  Influencing factors  Filtration effects  Remedial action  Conclusion

Remedial Action Stability study repeated – Phase 2

Samples for analytical submission placed into common glassware (made of soda lime) instead of scintillation vials Non silanised Do not act as an initiator for TM adsorption New time-points of analysis implemented; Days 0, 1 & 7 Analytical results;

Within the acceptable limits of ±10% of nominal conc. Day 0 No significant reduction in nominal conc. over time

Adsorptive effects using membrane filters reduced by; Saturating filter with small volume of formulation (1-2 mL) prior to sampling Filter adsorptive sites gradually occupied by the formulation mix Therefore, additional filtration will produce minimal adsorptive effects

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Conclusion

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Conclusion Scintillation vials contain Silanol functional groups

Undergo deprotonation when in contact with aqueous solutions Creates a electro-negative (-) charge inside container Attracts electro-positively (+) charged TMs Susceptible TMs undergo hydrolysis via nucleophilic reaction, causing adsorption Results in low TM % nominal conc.

Degree of adsorption influenced by formulation conc. More apparent at lower levels compared to higher levels Due to greater possibility of TM undergoing hydrolysis Issue overcome by replacing scintillation vials with common glassware (made of soda lime)

Adhesion of TM in formulation also influenced by membrane filters Via Van Der Waal’s interaction Attraction between opposite electro charges in TM and PVDF Filter Minimised by passing 1-2 mL of formulation through filter prior to sampling Saturates filter membrane adsorptive sites

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Questions?