Hospital Pharmacy - December 2017 - 754

754

Hospital Pharmacy 52(11)

Table 1. Forced Degradation Study Parameters.
Sample
1
2
3
4

Forced degradation treatment
Adjusted to pH 2 using 1-N HCl and incubated at
60°C
Adjusted to pH 12 using 1-N NaOH and incubated
at 60°C
Spiked with 3% hydrogen peroxide and incubated
at 60°C
Spiked with 3% hydrogen peroxide and exposed to
direct sunlight (ambient room temperature)

Evaluation of Tube Delivery
Three enteric feeding tubes, that is, PVC/18 Fr/48″, PVC/10
Fr/36″, and Polyurethane/10 Fr/36″, were evaluated for the
delivery of the prepared eslicarbazepine acetate suspensions.
Eslicarbazepine acetate suspensions were prepared using the
above method at 40 mg/mL. Feeding tubes were mounted to
a board to mimic the position the tube would be in a patient.
An oral syringe was attached to the top of the feeding tube,
the suspension (30 mL) was allowed to flow through the tube
via gravity, and the samples were collected after passing
through the tube for evaluation. Each tube type was tested 3
times using a clean/new tube each time (n = 3). Three dilutions were prepared from each sample using the method
described above. Dilutions were evaluated using the developed HPLC method, and samples were injected in triplicate
for each dilution. Peak area for each sample was compared
with a calibration curve developed each day.

Stability of Eslicarbazepine Acetate Suspension
The chemical stability assessment of the optimized suspension was performed at time 0 (immediately after preparation), at 24 h, and at 48 h after preparation. Samples were
stored in 2-Oz liquid-dispensing vials at room temperature,
and the suspensions were inspected visually for uniformity at
each time point. Each sample was analyzed by a stabilityindicating HPLC method described above. Three injections
were performed for each of the samples.

Results and Discussion
Preparation of Eslicarbazepine Acetate
Suspension
The results of particle size analysis of the powders obtained
by crushing the tablets using (1) Pillcrusher Medication
Delivery Syringe, (2) Silent Knight pill crusher, and (3) standard mortar/pestle are shown in Figure 1 and Table 2. In general, powders obtained after crushing the tablets by either
Pillcrusher syringe or the Silent Knight pill crusher exhibited
larger mean particle size (~400 μm). The statistical standard
deviation (indicating consistency between replicates) was

also found to be higher by these methods. Tablet components
formed a thick layer on the inner surface of the syringe.
Crushing the tablets using standard mortar/pestle appeared to
produce powders with significantly lower mean particle size
(~70 μm). The reproducibility and consistency of particle
size reduction was also found to be significantly better (SD:
~2.5 μm). Lower particle size is important to formulate a
physically stable suspension and avoid rapid sedimentation
of particles. Moreover, considering the fact that the suspensions were prepared with an intent to be delivered via enteral
feeding tubes (most with narrow lumen diameter), achieving
lowest possible particle size was critical. Based on the above
observations, standard mortar/pestle was selected as a preferred method for crushing Aptiom tablets to prepare the
suspensions.
Binary mixtures of ORA-Plus and water, in different
ratios, were evaluated for viscosity to assess the suitability
for preparing eslicarbazepine acetate suspensions. Figure 2
shows the viscosity profiles of these binary mixtures as a
function of spindle cone speed (shear rate). In general, the
viscosity of the mixtures decreased with increasing rate of
shear. This is known as "shear-thinning" and is a well-known
phenomenon observed with most non-Newtonian liquids.
For a given shear rate, the viscosity of the binary mixture
decreased in a near-linear manner with increasing ratio of
water. This was also expected considering the differences in
the native viscosities of ORA-Plus and water. Preliminary
experimental trials showed us that liquids with viscosities of
1000 cps or below demonstrated acceptable flow through the
enteric tubes. Thus, ORA-Plus:water ratios of 50:50 v/v or
lower were initially considered for the preparation of eslicarbazepine acetate suspensions.
The HPLC results confirmed that 40 to 60 mg/mL suspensions could be prepared accurately and reproducibly. Two
suspensions (40 or 60 mg/mL) were prepared using ORAPlus:water (50:50 v/v) as a suspending vehicle and evaluated
for viscosity. The results were compared with the viscosity
profile of ORA-Plus:water (50:50 v/v; Figure 3). In general,
the viscosity of the prepared suspensions was found to be
higher compared with the vehicle, significantly at the low
shear rates. At any given shear rate, suspension containing 60
mg/mL eslicarbazepine exhibited higher viscosity compared
with that containing 40 mg/mL eslicarbazepine. Based on the
viscosity profiles, the drug concentration of 40 mg/mL was
selected for suspension development and analysis. To further
confirm the suitability of suspension preparation, several
suspensions (40 mg/mL) were prepared using different ratios
of ORA-Plus:water as a vehicle. These suspensions were
analyzed for physical stability and viscosity to optimize the
choice of vehicle. Figure 4 shows the viscosity profiles of
these suspensions as a function of spindle cone speed (shear
rate). As observed with blank vehicles (ORA-Plus:water
binary mixtures), the viscosity of the mixtures decreased
with increasing rate of shear. For a given shear rate, the viscosity of the suspensions decreased in a near-linear manner

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