PRESERVATIVE DISTRIBUTION IN EMULSIONS by SYED JAMSHED ALI KAZMI B. Sc., Agra ...

128 Pages·2010·4.54 MB·English

PRESERVATIVE DISTRIBUTION IN EMULSIONS
by
SYED JAMSHED ALI KAZMI
B. Sc., Agra University, India, 1964
B. Pharm., University of Karachi, Pakistan, 1968
A THESIS SUBMITTED IN PARTIAL FULFILMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE IN PHARMACY
in the Division
of
Pharmaceutics
of the
Faculty of Pharmaceutical Sciences
We accept this thesis as conforming to the
required standard
THE UNIVERSITY OF BRITISH COLUMBIA
April 1971
In presenting this thesis in partial fulfilment of the requirements for
an advanced degree at the University of British Columbia, I agree that
the Library shall make it freely available for reference and study. I
further agree that permission for extensive copying of this thesis for
scholarly purposes may be granted by the Head of my Department or by
his representatives. It is understood that copying or publication of
this thesis for financial gain shall not be allowed without my written
permission.
Faculty of Pharmaceutical Sciences,
The University of British Columbia,
Vancouver, 8, Canada.
i
ABSTRACT
Until recently, evaluation of the effectiveness of preservatives in
emulsified systems has depended largely on time-consuming microbiological
techniques. Mathematical models have now been developed which enable the
amount of preservative necessary for adequate preservation to be calcu
lated. Determination of the physico-chemical parameters for these models
is again a time-consuming process, especially where complex emulsions are
involved. In the present work a three-chambered dialysis method has been
investigated. Using this method it is possible to determine the concen
tration of preservative in the various phases of an emulsion and thus the
total concentration required for adequate preservation.
Various factors affecting the distribution of preservatives between
oil and water and the interaction between preservatives and surfactant
are discussed. These factors are then related to the problem of the
distribution of a preservative in an oil in water emulsion system.
Methodology used to evaluate the various physico-chemical parameters
is reviewed and equations for representing the results are discussed.
The distribution of benzoic acid between peanut oil and water and
mineral oil and water systems was studied over a wide concentration
range. The interaction of benzoic acid with aqueous solutionsof the
nonionic surfactant cetomacrogol was studied using solubility and equili
brium dialysis techniques. The interaction of various other preserva
tives with aqueous solutions of the nonionic surfactant cetomacrogol was
examined. A comparison was made of various methods of expressing this
ii
interaction. It is suggested that the Scatchard equation is the most
satisfactory equation for describing the binding data. Binding para
meters determined from a Scatchard plot in the concentration range of
free preservative appropriate for antimicrobial activity were used to
calculate the total concentration of preservative required in the sur
factant solution.
A three-chambered dialysis cell was used to estimate the distribu
tion of benzoic acid between the oil phase and the aqueous phase of oil
in water emulsions containing peanut oil or mineral oil. The method
also differentiates between preservative bound, or solubilized, by the
surfactant and free in the aqueous phase. The distribution data was
plotted on a three-dimensional graph from which the total concentration
of preservative needed to provide a given free concentration in the
aqueous phase can be determined. Results from the dialysis method agree
closely with those calculated using mathematical models for preservative
distribution. Hence the three-chambered dialysis method provides a
relatively simple direct method of determining the required preservative
concentration without recourse to mathematical models.
Supervisor.
i i i
TABLE OF CONTENTS
Page
I. INTRODUCTION 1
II. LITERATURE SURVEY 4
A. Distribution of Preservatives in Oil-Water Systems 4
(a) Factors affecting antimicrobial activity of
preservatives in oil-water systems 4
(b) Representation of distribution data 11
B. Interaction of Preservatives with Nonionic Surfac
tants 18
(a) Potentiation of preservative activity 18
(b) Inactivation of preservative activity 19
(c) Mechanism of inactivation 21
(d) Sites of interaction in surfactant micelle 23
(e) Representation of interaction data 25
C. Distribution and Antimicrobial Activity of Preserva
tives in Emulsified Systems 28
D. Prediction of Total Preservative Concentration Re
quired in an Emulsion 30
E. Methodology 34
(a) Distribution of preservatives in oil-water
systems 34
(b) Interaction of preservatives with nonionic
surfactants 35
(c) Distribution of preservatives in oil-water-
surfactant systems 43
III. EXPERIMENTAL 46
iv
Page
A. Apparatus 46
B. Materials 47
C. Temperature 48
D. Analysis of Benzoic Acid 48
E. Analysis of Surface-Active Agents 48
(a) Polarographic analysis 48
(b) Method of Crabb and Persinger 49
F. Permeability of Cellophane Membranes to Cetomacrogol 51
G. Membrane Binding 54
H. Distribution of Benzoic Acid in Oil-Water Systems 55
I. Interaction of Preservatives with Cetomacrogol 55
J. Distribution of Benzoic Acid in Oil-Water-Surfactant
Systems 57
(a) Preparation of emulsions 57
(b) Two-chambered dialysis technique 57
(c) Three-chambered dialysis technique 57
IV. RESULTS AND DISCUSSION 61
A. Analysis of Surface-Active Agents 61
B. Permeability of Cellophane Membranes to Cetomacrogol 65
C. Membrane Binding 68
D. Distribution of Benzoic Acid in Oil-Water Systems 68
E. Interaction of Benzoic Acid with Cetomacrogol 71
F. Representation of Preservative-Surfactant Inter
action Data 74
G. Distribution of Benzoic Acid in Oil-Water-Surfactant
Systems 92
(a) Two-chambered dialysis technique
(b) Three-chambered dialysis technique
(c) Validity of two- and three-chambered dialysis
techniques
(d) Applications of three-chambered dialysis technique
V. SUMMARY AND CONCLUSION
VI. REFERENCES
LIST OF TABLES
1. Proportions of benzoic acid undissociated at various pH
values
2. Influence of partition coefficient and phase-volume ratio on
concentration of preservative in aqueous and oil phase of a
two-phase system
3. Minimum inhibitory concentrations and binding parameters for
the interaction of preservatives with cetomacrogol
4. Validity of three dimensional calibration curve for the dis
tribution of benzoic acid between peanut oil-water-cetomacro-
gol systems at various oil-water ratios
5. Validity of three dimensional calibration curve for the dis
tribution of benzoic acid between peanut oil-water-cetomacro-
gol systems at various cetomacrogol concentrations
vii
LIST OF FIGURES
Page
1. Possible sites of incorporation of solubilizate in a
micelle 24
2. Solubility of preservative as a function of surfactant
concentration 40
3. Polarographic current voltage curves 50
4. Dynamic dialysis method 53
5. Two-chambered dialysis cell 59
6. Three-chambered dialysis cell 60
7. Polarographic determination of cetomacrogol 62
8. Polarographic determination of surface-active agents 63
9. Colorimetric determination of cetomacrogol ' 64
10. Permeability of Fisher cellophane membrane to cetomacrogol
in dynamic dialysis 66
11. Permeability of cellophane membranes to cetomacrogol in
equilibrium dialysis 67
12. Binding of benzoic acid with Mi Hi pore VS membrane 69
13. Binding of cetomacrogol with Millipore VS membrane 70
14. Plot of pH-independent partition coefficient of benzoic
acid versus the aqueous concentration of unionized benzoic
acid 72
15. Plot of pH-dependent partition coefficient of benzoic
acid in aqueous phase 73
16. Variation of apparent partition coefficient with free pre
servative concentration for the partition of preservative
between micelles and aqueous phase of cetomacrogol 77
17. Ratio of Total/Free propyl p-hydroxybenzoate as a function
of cetomacrogol concentration at 25° 79
18. Ratio of Total/Free benzoic acid as a function of ceto
macrogol concentration at 30° 80
Langmuir-type plot for the interaction of preservatives
with cetomacrogol solutions: Benzoic acid and Parahydroxy-
benzoic acid
Langmuir-type plot for the interaction of preservatives
with cetomacrogol solutions: Methyl p-hydroxybenzoate;
Propyl p-hydroxybenzoate and Chioroxylenol
Double-reciprocal plot for the interaction of preserva
tives with cetomacrogol solutions: Benzoic acid and
Parahydroxybenzoic acid
Double-reciprocal plot for the interaction of preserva
tives with cetomacrogol solutions: Methyl p-hydroxyben-
zoate; Propyl p-hydroxybenzoate and Chioroxylenol
Scatchard plot for the interaction of preservatives with
cetomacrogol solutions
Variation of free benzoic acid concentration [Df], in the
aqueous phase of an emulsion with total benzoic acid con
centration [D] for an o/w peanut oil emulsion stabilized
with cetomacrogol
Ternary graph of the distribution of benzoic acid in an o/w
peanut oil emulsion stabilized with cetomacrogol
Ternary graph of the distribution of benzoic acid in an o/w
mineral oil emulsion stabilized with cetomacrogol
Three-dimensional graph of the distribution of benzoic acid
in an o/w peanut oil emulsion stabilized with cetomacrogol
Three-dimensional graph of the distribution of benzoic acid
in an o/w mineral oil emulsion stabilized with cetomacrogol
Modified three-dimensional graph of the distribution of ben
zoic acid in an o/w peanut oil emulsion stabilized with
cetomacrogol
Modified three-dimensional graph of the distribution of ben
zoic acid in an o/w mineral oil emulsion stabilized with
cetomacrogol