Injectable Pharmaceutical Product Development for a Poorly Soluble Drug using

Multiple Formulation Methodologies

J. J. Luo, Ph.D., Victoria Tropina, Brian Woodrow, Ph.D., Craig Davies-Cutting, Ph.D.
AAPS Annual Meeting-2010

Catalent Pharma Solutions, 160 Pharma Drive, Morrisville, North Carolina, USA, 27560

Purpose
Significant formulation challenges exist as a result of the increasing
number of poorly soluble drugs in development. Approximately 40% of
drugs in development, and 60% of compounds from discovery are
poorly soluble, i.e. below 0.1 mg/L, and likely to result in limited
bioavailability in their therapeutic application [Muller, et al., Int. J. of
Pharmaceutics, 269, (2004), 293-302].
The purpose of this study was to explore the impact of emulsion,
liposomal liquid and lyophilized liposomal formulations on drug loading,
physical stability and chemical stability.

CASE 1: EMULSION FORMULATION

A formulation emulsified with Soybean oil and Polysorbate 80 drug
loadings of up to 1 mg/mL were achieved, as shown in Figure 1 (A).
CASE 2: LIPOSOMAL LIQUID FORMULATION
A phospholipid mainly containing Phosphatidyl Choline was used to
form liposomal liquids from 1 to 2.5 mg/mL, as shown in Figure 1 (B).
Figure 1 Emulsion and Liposome Formulations

Methods

The DLS results for both emulsion and liposome had a Z-average
(indicating average particle size) that appeared to have no change over 5
days, approximately 120 nm with a small polydisperse index (PDI) of
around 0.28, indicating nearly mono-size distribution.
However, as shown in Table 2, a gel was formed at 2.5 mg/mL for the
liposome system. The liposomal formulation exhibited chemical stability
under the same storage conditions whereas 5 % degradation was
observed for the emulsion in 15 days.
Table 2 Formulation Stability in Active Concentration (mg/mL)

Formulation - Drug was added to an appropriate vehicle, heated to

approximately 60 C, and homogenized to obtain a stable dispersion.
The vehicle was prepared by adding appropriate excipients to water
for injection. The excipients utilized perform different functions in the
formulations, for example, Lactic Acid as an apparent buffer,
Propylene Glycol as a solubility enhancer, Soybean Oil as a lipophilic
solvent for emulsion formulation, Polysorbate 80 as an emulsifier, a
phospholipid as a liposomal constructor and stabilizer for liposomal
formulation, and Sucrose as lyoprotectant and stabalizer for
lyophilization formulation. The formulated liquids were subject to
sterile filtration. The liposomal formulation was subsequently
lyophilized with the lyoprotectant to aid stability.
Analytical The formulations were evaluated for physical stability via
visual examination, dynamic light scattering (DLS) and spike study.
Chemical stability was evaluated via a HPLC assay.

(A)

(B)

No precipitation was observed with either emulsion or liposomal

dispersion formulations when stressed from pH 4 to 7 each in a spike
study.
Figure 2 DLS Result of Emulsion Formulation

Results and Discussion

Liquid
Formulation
at 5 C

Day 0

Day 7

Day 15

Conclusion

Liposome
(1 mg/mL)

0.98

0.98

0.99

No Change

Liposome
(2.5 mg/mL)

2.51

2.63

Gel
formed

Not
Physically
Stable

Emulsion
(1 mg/mL)

1.02

0.98

0.97

Some
Degradation

Emulsion
(2 mg/mL)

2.14

Gel
formed

Gel
formed

Not
Physically
Stable

Two types of liquid formulation including emulsion and liposome, and

one type of lyophilized liposome were prepared; and the formulation
recipes are shown in Table 1.
CASE 3: LYOPHILIZED LIPOSOME

Table 1 Formulation Recipe

Formulation
(w/w)

Emulsion

Liquid
Liposome

Lyophilized
Liposome

Poorly Soluble
API

1 mg/mL

1 mg/mL

1-2.5
mg/mL

Lactic Acid

0.5%

0.5%

0.5%

Propylene
Glycol

1.0%

1.0%

1.0%

Lyophilization was thus

conducted to enable formulation
at 2.5 mg/mL without gel
formation. The moisture level for
the lyophilized product was 0.1
%w/w and the reconstitution time
less than 2 minutes. The
lyophilized formulation exhibited
no change after 2 weeks stability
storage.

Phospholipid

1.0%

1.0%

1.0%

Conclusions

Sucrose

2.0%

2.5%

4.0%

Polysorbate 80

0.1%

0.1%

0.1%

Soybean Oil

2.0%

Figure 3 DLS Result of Liposome Formulation

Figure 4 Lyophilized Powder

Multiple formulation methodologies were evaluated to address poor drug

solubility including emulsion, liposomal liquid and lyophilized liposome.
Drug loadings up to 2.5 mg/mL were achieved with the lyophilized liposome
approach with superior stability to either the emulsion or the liquid liposomal
formulation.

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