(767d) HPMC Cloud Point: Exploring Hydroxypropylmethyl Cellulose Behavior in Pharmaceutical Formulations

HPMC
cloud point: Exploring hydroxypropylmethyl cellulose behavior in pharmaceutical
formulations

Maryam
Mohammadpour^1,2,*, Brian Kerins¹, Mary Ellen Crowely¹, Gavin W. Walker², Abina M. Crean^1,2

School of
Pharmacy, University College Cork, Ireland¹

Synthesis & Solid State
Pharmaceuticals Centre (SSPC), Bernal Institute, University of Limerick, Ireland²

 *Tel: + 353 (21) 4901683,
email: marym.mohammadpour@ul.ie

INTRODUCTION

Hydroxypropylmethyl cellulose (HPMC) is
widely used in pharmaceutical applications as a sustained release agent (Viriden, Wittgren et
al. 2011),
tablet coating, nanoparticulate stabilisers and nucleation inhibitor (Ghosh, Bose et
al. 2011). In
these applications its gelation behaviour is key to its performance and
therefore needs to be understood within each system. Aqueous solutions
of HPMC display two characteristic temperatures: a thermal gelation temperature
(TGT) and a lower critical solution temperature (LCST). The gelation behaviour of HPMC is
influenced by the HPMC degree of substitution, formulation additives (such as
salts, surfactants, drug molecules) and temperature (Zhang, Wang et al. 2015). [i]

HPMC begins to
precipitate out of solution at the LCST due to the loss of water of hydration
at increased temperatures (Viridén,
Wittgren et al. 2011). This phase separation into a polymer
rich and polymer depleted phase, caused by association of hydrophobic groups
leading to aggregation, allows for the cloud point to be determined as the
polymer rich phase is capable of scattering light. Though there seems to be no direct
relationship between TGT and cloud point, it seems that both properties are
affected by electrolytes in the same manner i.e. if an electrolyte increases
the TGT, it will also increase the cloud point (Mitchell, Ford et al.
1990).

The objective of this paper is to
demonstrate the ability of cloud point measurements to identify the impact of
formulation additives on the behaviour of HPMC within formulations during
dissolution. The additives investigated include; a surfactant, docusate sodium
(DOSS) and a model drug carbamazepine. The goal of this work is to use cloud
point measurements to understand formulation interactions with HPMC which will
increase understanding of variability in formulation behaviour during dissolution.

Materials and Methods

The HPMC grade investigated was HPMC
substitution type 2910, label viscosity 3 cp. In comparison a 2^nd
HPMC derivative was also investigated, HPMCAS Grade AS-MG viscosity type 3 cp.
HPMCAS is a cellulose polymer which does not exhibit a cloud point. The goal of
the study was to investigate both polymers in aqueous systems with and without
docusate sodium and carbamazepine to assess the additive effect on cloud point
behaviour.

Aqueous polymeric solutions were
prepared by adding HPMC to an aqueous solution of additive while stirring with
a magnetic stirrer at 500 rpm. The solutions were made up to the required
volume with ice cold deionised water and left mixing for 20 minutes. The solution
was degassed by a sonicator for one hour and then moved to a refrigerator to
hydrate overnight.

A Chirascan circular dichroism
spectrometer performed cloud point assays. Percentage transmission was examined
at 800nm over a range of 25 – 91 ˚C at a rate of 1.0˚C/min.
Sample was present in a  0.5mm quartz cuvette. An air background calibration
was carried out prior to testing each day.

Results

To ensure the accuracy of the
produced results a centre point (6% HPMC, 0.5% DOSS) was ran in triplicate over
3 separate days. The average CP was calculated to be 73.25 ± 0.725 ˚C. The
low standard deviation indicates the Chirascan instrument is capable of
generating reproducible CP measurements.

There is a clear trend evident that
as the concentration of DOSS increases the the CP increases. This we attribute to
the increased energy needed to overcome the solubilisation of the hydrophobic
groups of the HPMC by the surfactant (Figure 1). When ionic surfactants and non-ionic
polymers are mixed, two competing phenomena take place: 1) Self aggregation of
surfactant molecules to form micelles or 2) interaction of individual
surfactant molecules with monomer units of the polymer chain (Acevedo, Takhistov et
al. 2014). The
free surfactant molecules bind to the hydrophobic parts of the polymer through
adsorption until a state of saturation is reached. The priority binding of the
surfactant produces polar outshells, increasing the energy barrier for the
crosslinking of the HPMC chains to occur, by hindering the free access to HPMC
chains. The thermal energy requirements for dismantling this shell and for the
aggregation of the polymer is determined by the chemical structure and
electrostatic interaction between the surfactant and HPMC (Joshi 2011).

Figure 1: The effect of varying concentration of DOSS
on HPMC cloud point (Cloud point was reached when he overall
% transmittance of light reaches 50% of that compared to the same sample at
25˚C (Silva,
Pinto et al. 2008).

Additional results will be presented
looking at the effect of carbamazepine level on HPMC cloud point. Also the
corresponding behaviour of HPMCAS polymer will be presented. Studies to date
have not detected a cloud point for aqueous solutions of HPMCAS alone. To show
the relevance of these cloud point studies, dissolution studies was be present
from a range of these formulation compositions.

Conclusions

Formulation additives such as
docusate sodium were shown to positively influence the cloud point of HPMC. Future
work will explore how this alteration of the polymer self-assembly behaviour
and cloud point can inform the HPMC-formulation behaviour during dissolution
studies.

References

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hydroxypropylmethylcellulose solutions with SDS and hydrophobic drug
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Joshi, S. C. (2011).
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Mitchell, K., et al.
(1990). "The influence of additives on the cloud point, disintegration and
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Journal of Pharmaceutics 66(1): 233-242.

Silva, S. M., et al.
(2008). "Aggregation and gelation in hydroxypropylmethyl cellulose aqueous
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Viriden, A., et al.
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Zhang, L., et al.
(2015). "Rheological and gel properties of hydroxypropyl
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