(330d) Solution Coating of Pharmaceutical Nanothin Films and Multilayer Nanocomposites with Controlled Morphology and Polymorphism

With the advent of combinatorial chemistry and high throughput
screening, active pharmaceutical compounds (APIs) with low aqueous solubility
have become increasingly pervasive in drug development pipeline. The
formulation challenges of these drug candidates, that exhibit poor
bioavailability, often encumber their route to pharmacy shelf from lab-bench.
This issue is one of the major contributing factors for the skyrocketing cost
of drug development today, which has reached over $1.3 billion per drug on
average.¹

In recent years, nanosizing is rapidly emerging as an effective
and versatile method for enhancing solubility and thus the bioavailability of
poorly aqueous soluble APIs. Previous studies have indicated that confining
crystalline APIs to the nanoscale dimension exhibit increased solubility and
enhanced dissolution, owing to large surface area and high surface curvature.² However,
current industrially compatible nanonization processes mostly utilize top-down
approaches where bulk crystals are broken down via mechanical forces. These
methods of nanosizing are energy inefficient and require long processing time
while other methods such as formation of polymeric micelles and nanoemulsions
have poor stability and their processing mandates expensive instrumentation and
high concentration of emulsifiers, respectively. In this scenario, industrially
compatible techniques for large-scale manufacturing of API crystals with
consistent crystal size distributions smaller than few hundred nanometers are
urgently needed.

In this talk, we present meniscus-guided solution coating as a new
technique of producing pharmaceutical films and multilayered composites at the
nanoscale. This facile technique has previously been employed for depositing
semi-conductor nanothin films for printed electronic devices and enables easy
modulation of film morphology and polymorphism.^3-5 While API
crystal morphology determines its dissolution rate, the packing modes of API
molecules play crucial role in controlling the bioavailability, processability
and stability of the APIs.⁶ By changing simple process
parameters such as API solution concentration and coating speed in order to
modulate the driving forces involved in the film deposition, we demonstrate
control of a) film thickness over more than two orders of magnitude (30 nm to
1.5 µm), b) thin film morphology and c) crystal polymorphism. In fact, solution
coating technique also allowed us to systematically trap metastable polymorph
in the film of a poorly soluble API. The controlled crystallization of
metastable polymorph is advantageous in the case of poorly aqueous soluble APIs
because metastable polymorphs usually exhibit higher solubility rate owing to
their higher free energy.

Furthermore, we performed layer-by-layer solution coating of
alternating nanometer-thick films of an API and a biocompatible polymer in a
multilayered fashion, in a variety of substrates. This demonstrates the
potential of solution coating technique in formulation of API doses consisting
of multiple drugs which enables controlled and sequential release of each of
the components as per patientÕs need, catering to the enormous enthusiasm of
modern medical research towards personalized medicine.

References

1.         DiMasi,
J. A.; Grabowski, H. G.; Hansen, R. W., Innovation in the pharmaceutical
industry: New estimates of R&D costs. J Health Econ 2016, 47,
20-33.

2.         Kaptay,
G., On the size and shape dependence of the solubility of nano-particles in
solutions. International Journal of Pharmaceutics 2012, 430
(1-2), 253-257.

3.         Diao,
Y.; Shaw, L.; Bao, Z. A.; Mannsfeld, S. C. B., Morphology control strategies
for solution-processed organic semiconductor thin films. Energ Environ Sci 2014,
7 (7), 2145-2159.

4.         Diao,
Y.; Tee, B. C. K.; Giri, G.; Xu, J.; Kim, D. H.; Becerril, H. A.; Stoltenberg,
R. M.; Lee, T. H.; Xue, G.; Mannsfeld, S. C. B.; Bao, Z. N., Solution coating
of large-area organic semiconductor thin films with aligned single-crystalline
domains. Nature Materials 2013, 12 (7), 665-671.

5.         Diao,
Y.; Lenn, K. M.; Lee, W. Y.; Blood-Forsythe, M. A.; Xu, J.; Mao, Y. S.; Kim,
Y.; Reinspach, J. A.; Park, S.; Aspuru-Guzik, A.; Xue, G.; Clancy, P.; Bao, Z.
N.; Mannsfeld, S. C. B., Understanding Polymorphism in Organic Semiconductor
Thin Films through Nanoconfinement. J Am Chem Soc 2014, 136
(49), 17046-17057.

6.         Singhal,
D.; Curatolo, W., Drug polymorphism and dosage form design: a practical
perspective. Advanced Drug Delivery Reviews 2004, 56 (3),
335-347.