Factors influencing ester formation between a weakly acidic compound
and polyethylene glycol solvents used in softgel fill formulations
Anwaar Naqvi *, Sridhar Gumudavelli, Prasanna Butchireddygari, Anna Eidelman, Rampurna Gullapalli
Pharmaceutics International, Inc., www.pharm-int.com, 10819 Gilroy Road, Hunt Valley, MD 21031
p
g Author: [email protected]
q @p
*Corresponding
Poster No. W4216 (Hall C), October 26, 2011 (8:00 am- 12:00 pm)
METHODS
ABSTRACT
Title Factors influencing ester formation between a weakly acidic compound and polyethylene glycol solvents used in
Softgel fill formulations.
Purpose Weakly acidic compounds solubilized in polyethylene glycol (PEG) vehicles are known to undergo
esterification reactions. Minimizing these reactions during manufacturing and shelf-life is critical to improving the
quality of products. The presentation discusses the influence of various formulation factors on the stability and rate and
extent of ester formation between ibuprofen (chosen a model weakly acidic compound) and PEG 600.
Methods Solubility and ester formation of ibuprofen in PEG 600 were evaluated as a function of extent of in-situ
ionization of ibuprofen with KOH. Chemical stability and extent of ester formation at 60°C were followed overtime
using a validated HPLC analytical procedure. These profiles were compared with solutions prepared with preformed
powder blends consisting of ibuprofen and ibuprofen potassium salt in various proportions.
Results Solubilized ibuprofen, in its unionized form, produced esters with PEG 600 extensively which increased with
time (solution apparent pH 4.9; esters 8.8% @ 15day; 14.5% @ 30day). The extent of ester formation reduced
proportionally with increasing in-situ ionization of ibuprofen with KOH and plateaued at 50% ionization (apparent pH
≥ 8.8; esters 1.0-1.6% @ 30day). In contrast to unionized ibuprofen solutions, ≥ 50% ionization of ibuprofen also
prevented formation of esters during the time of preparation of solutions (esters 0.12% unionized versus 0.00% @ ≥
50% ionization). Use of a preformed powder blend consisting of ibuprofen and ibuprofen potassium salt (50:50) also
resulted in PEG 600 solutions with ester profiles (apparent pH 9.2; esters 0.0% @ initial; 1.16% @ 30day) similar to
those of solutions prepared using in-situ ionization technique. A slight decrease in the apparent pH was also observed
for all solutions upon storage at 60°C.
Conclusion Optimized ionization reduced ibuprofen ester formation with PEG 600 during manufacturing and stability
evaluation of the product.
Influence of Hydroxyl Vehicles on Ibu-Ester Formation
Solubilization of Ibuprofen in PEG 600 with in-situ neutralization:
• Prepare suspensions of 40% w/w Ibu in PEG 600,
• Heat suspensions to 50±5°C with mixing,
• Mix with aqueous KOH solutions to yield various in-situ neutralization of Ibu,
• Place solutions at 60°C for stability evaluation,
• Analyze solutions for Ibu and Ibu-PEG esters using a validated HPLC method
Ibu-PEG Esters
% Ibu Neutralization
Column: Zorbax Eclipse XDB-C8, 5 µm, 150 mm x 4.6 mm
Mobile Phase: Acetonitrile:0.01M Phosphoric acid (37:63)
Flow Rate: 2.0 mL/min.
Column Temperature: 22°C
Injection Volume: 30µL
Detection Wavelength: 220 nm
Weakly acidic compounds solubilized in polyethylene glycol (PEG) vehicles are known to undergo
esterification reactions. Minimizing these reactions during manufacturing and shelf-life is critical to
improving the quality of products. The presentation discusses the influence of various formulation factors on
the stability and rate and extent of ester formation between ibuprofen (Ibu), chosen a model weakly acidic
compound, and PEG 600.
0
0.23
9.23
0
0.15
1.43
0
0.13
1.05
0.83
0.14
0.90
0.65
PEG 600 with 5% Glycerin
50
PEG 600 with 5% Propylene glycol
50
Ibuprofen Standard.
I fl
Influence
off Fill Compounding
C
di Procedure
P
d
on Ibu-Ester
Ib E t F
Formation
ti in
i Soft
S ft Gelatin
G l ti Capsules
C
l (Softgels)
(S ft l )
Stability at 40°C/75% RH
Glycerin
PEG
Ibuprofen
2 Month
3 Month
Ibu-PEG 600
0.00
0.67
0.95
Ibu-Glycerin
0.10
0.21
0.31
In-situ Neutralization
Preformed Ibu and Ibu-Potassium Salt Blend
Fill
Sorbitol
1 Month
Ibu in PEG 600 @ 60°C‐2Wks.
Ibu in PEG 600 + 5% Propylene glycol @ 60°C‐2Wks.
Plasticizer(s)
15 Day at 60°C
50
Ester Type
INTRODUCTION
Other Esters
15 Day at 60°C
PEG 600 with No Glycerin or Propylene glycol
HPLC PROCEDURE
•
•
•
•
•
•
After Manufacturing
Ibu in PEG 600 + 5% Glycerin @ 60°C‐2Wks.
Ibu-PEG 600
0.30
0.37
0.50
Ibu-Glycerin
0.05
0.10
0.14
RESULTS
Solubilized Ibu, in its unionized form, produced esters with PEG 600 extensively which increased with time.
ƒ
Apparent pH 4.9; esters 8.8% @ 15day; 14.5% @ 30day.
Extent of ester formation reduced proportionally with increasing in-situ neutralization of Ibu with KOH and
plateaued at 50% neutralization.
ƒ
Apparent pH ≥ 8.8; esters 1.0-1.6% @ 30day.
ƒEvaluate solubility of Ibu in PEG 600 as a function of extent of in-situ neutralization of Ibu with KOH.
% Ibu Neutralization
ƒFollow chemical stability and extent of ester formation at 60°C overtime using a validated HPLC analytical
procedure.
ƒCompare chemical stability and extent of ester formation between (a) solutions prepared with in-situ
neutralization and (b) solutions prepared with preformed powder blend consisting of Ibu and Ibu-potassium
salt.
I contrast to unionized
In
i i d Ibu
Ib solutions,
l i
≥ 50% neutralization
li i off Ibu
Ib also
l preventedd formation
f
i off esters during
d i
the time of preparation of solutions.
ƒ
Esters 0.12% unionized versus 0.00% @ ≥ 50% neutralized.
Influence of % Neutralization of Ibu on Ibu-PEG Ester Formation
OBJECTIVES
Ibu-PEG Esters
After Manufacturing
15 Day at 60°C
30 Day at 60°C
In-situ Neutralization
Use of a preformed powder blend consisting of Ibu and Ibu-potassium salt (50:50) also resulted in PEG 600
solutions with ester profiles similar to those of solutions prepared using in-situ neutralization technique.
ƒ
Esters 0.0% @ initial; 1.16% @ 30day for preformed blend
ƒ
Versus Esters 0.0% @ initial; 1.46% @
30day for in-situ neutralization.
0
0.12
8.82
14.51
30
0.08
3.68
6.27
35
0.17
3.73
6.34
40
0.10
2.86
5.06
CONCLUSION
CONC
US ON
45
0.09
1.89
3.48
50
0
0.75
1.46
Optimized neutralization reduced Ibu ester formation with PEG 600 during manufacturing and stability
evaluation of the product.
55
0
0.84
1.55
60
0
0.54
1.03
0
0.59
1.16
Preformed Ibu and Ibu-Potassium Salt Blend
50
A slight decrease in the apparent pH was also observed for all solutions upon storage at 60°C.