(667b) Continuous Crystallization for Production of Drug Nanosuspensions

Keywords: nanoparticles,
crystallization, bioavailability.

Presented here
is a novel technology (PureNano^TM) for continuous crystallization
and large scale production of drug mirco- or nano- particles with tailored
properties, in a highly efficient matter. The technology allows for turbulent
mixing of crystallization precursors (solvent, antisolvent, seeds, etc.), the
formation of turbulence eddies in the range of 25-50nm, and therefore high
spatial uniformity of supersaturation. In addition, PureNano^TM
allows for precise control of mixing times and intensity, and temperature
history. Therefore it allows for precise control of the crystallization
process. The energy for crystallization required by this method may be orders
of magnitude lower than the energy demands of conventional methods for creating
micro- and nano- suspensions, which involve breaking large crystals to smaller
entities. In addition, crystallization times may be greatly reduced through
minimizing of diffusion limitations.

Background.
Estimates suggest that each year roughly half of all newly formulated drugs
having potentially high pharmacological value will have little chance to make
it beyond the laboratory and into marketplace. Drug formulations exist
basically as either emulsions or suspensions, the latter consisting of non-
water soluble (hydrophobic) active pharmaceutical ingredients (APIs) suspended
in a liquid. Drug suspensions are of great interest because of their high bioavailability
which significantly reduces the amount of drug that needs to be delivered as
compared to drug emulsions. However, formulation difficulties may still exist
since the particle size of the solid API plays a crucial role in 1) the
stability of the suspension and 2) the safe delivery of the drug.

Certain
crystallization processing technologies claiming to produce stable
nano-particles are mainly experimental and may have major shortcomings. As an
example, low pressure impinging jet technology^[1] is characterized
by low flow rates, low jet velocities, and therefore low energy. These jet
velocities are over two orders of magnitude lower than velocities used in PureNano^TM.
Low pressures and low energy levels are associated with large particles and inability
of the technology to produce stable particles and handle high solid loadings
without plugging or fouling. Another example is use of supercritical carbon
dioxide spray processing technology. This technology has been proven to be
impractical for manufacturing because it is not scalable and is highly energy
intensive.

Recent
breakthroughs in continuous crystallization technology now enable
pharmaceutical and biotechnology companies to overcome issues related to
stability and safe drug delivery.  Microfluidics International Corporation is
marketing this technology as their PureNano^TM Continuous
Crystallizer and associated process protocols. Consequently such systems take
on an important role in the formulation and the continuous manufacturing of
high purity stable nano-suspensions which is not always achievable with
conventional particle size reduction methods.The PureNano^TM Crystallizer,
which incorporates a scalable mixing chamber, is an energy-efficient method. A
case study is presented later that demonstrates the success of this system in
formulating a nano-suspension cancer drug that conventional particle size
reduction methods were unable to achieve.

Principal
of Operation/Applications. Applications best suited for the PureNano^TM
 Crystallizer are dependent upon the length of time for crystallization to
occur. These ?resident? times are critical to the crystallization process and
are dependent upon the API involved, which may require residence times that
range from a few hundred microseconds to several hundred milliseconds. To
accommodate this range of times, multiple system configurations are available.

Figure 1. The PureNano Crystallizer configured with coaxial feed

To illustrate
the principal of operation we selected the coaxial feed system as depicted in
Fig 1. The API is first dissolved in a predetermined solvent, Solution 1, and
is placed in one of the two inlet reservoirs. Solution 2, the ?anti-solvent,?
which in many cases may be water, is placed in the second reservoir as shown. This
feed configuration allows controlled pre-mixing of the two streams within a
?macro-mixing? zone prior to entering the mixing chamber. This pre- mixing
occurs for a predetermined period of time within the macro-mixing zone, usually
in the order of several milliseconds, creating a small number of product nuclei
for ?seeding?. The feed rates, solution ratios and mixing intensities within
the coaxial feed are precisely controlled with metering pumps. This pre-mixed
solution is then pressurized and subsequently enters the mixing chamber as a
single stream which is internally split into two jets that collide. This forces
interact at the nano-scale resulting in a continuous output flow of a stable
high purity nano-suspension.

As previously
reported by Microfluidics, the PureNano^TM Crystallizer has been
successful in producing stable nano-suspensions in the laboratory^[2,3]
where conventional particle size reduction methods were proven to be
unsuccessful. In all PureNano^TM Crystallizer configurations, post
processing may be necessary to prevent crystal growth or to alter crystal habit
and/or morphology.

Case Study.
Presented here are preliminary results from an ongoing collaborative effort
with a well known pharmaceutical company in an effort to successfully formulate
a cancer drug identified here as Compound V.  To increase bioavailability, it
was determined that the drug needed to be delivered intravenously in the form
of a nano-dispersion. .

Figure 2. Results with conventional particle size
reduction method

Microfluidics
conventional ?top down? particle size reduction technology and PureNano were
used for the production of the nano-suspension. The required particle size was
a median size less than 200 nanometers. Using the top down method, a suspension
of the drug in water was prepared and processed using a Model 110EH-30
Microfluidizer processor. After 40 passes through the processor, the mean
particle size of the API was reduced from 1.401 microns to 401 nanometers with
no further particle size reduction resulting with additional passes (Fig. 2).
The resulting suspension was unacceptable; it did not meet the stability
requirements.

Figure 3. Results with the PureNano Crystallizer  

Using a
PureNano^TM Crystallizer in conjunction with our nano-suspensions
development protocol, a continuous crystallization process was developed.
Compound V was dissolved in a solvent, polyethylene glycol (PEG), at various
concentrations (Fig. 3), in the range of 20-120mg/ml. This stream was mixed
with the antisolvent stream (water) at the appropriate proportions using a
PureNano^TM Crystallizer processor. The ratio of the antisolvent to
solvent streams varied from 1:4 to 1:10 producing various degrees of
supersaturation. A stable nano-suspension with a median particle size of 102
nanometers was achieved in a single pass. The particle size distribution was
well within specifications.

References:

[1]    Johnson, B.; Prud'homme, R. Chemical Processing and
Micromixing in Confined Impinging Jets. AICHE J. 2003, 49,
2264-2282.

[2]  Panagiotou, T.; Fisher, R. Form
Nanoparticles via Controlled Crystallization.    CEP, 2008, 33-39C.

[3]  Panagiotou, T.; Mesite, S.; Fisher,
R. Production of Norfloxacin Nanosuspensions Using Microfluidics Reaction
Technology through Solvent/Antisolvent Crystallization Ind. Eng.
Chem. Res., 2009, 48 (4), 1761-1771.