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The Process
The basic process by which CritiTech
produces sub-micron drug particles involves a procedure referred
to as Precipitation with Compressed Antisolvent (PCA).
The PCA process is based upon the unique properties of carbon
dioxide when that gas is raised above its critical pressure
(Pc) and temperature (Tc) (i.e., supercritical CO2).
The critical pressure (or temperature) of a compound is that
pressure (or temperature) above which the material undergoes
a phase transition. In the case of carbon dioxide, the
critical temperature is a relatively mild 31.1º C and the
critical pressure is 73.8 bar, or about 1,100 psi.
Supercritical CO2 has properties that are
mid-way between those of a gas and those of a liquid.
Along a near-critical isotherm (between 1.0 and 1.2 Tc), the
density, transport properties (e.g., viscosity, diffusivity),
and other physical properties (e.g., dielectric constant,
solvent strength) can be varied in a continuum from gas-like
to liquid-like with relatively small changes around the critical
pressure (0.9 - 2.0 Pc). The net result is that at selected
pressures and temperatures supercritical CO2 has nearly the
diffusivity of a gas and the viscosity of a liquid.
Carbon dioxide is a non-polar solvent.
This property, and the above-mentioned properties combine
to make supercritical CO2 an ideal medium for pharmaceutical
processing. Processing can take place at temperatures
lower than 35º C and at pressures, which although high, are
not unusual in the chemical processing arena.
Particle Formation Using Supercritical
Carbon Dioxide
The Company’s process takes advantage of the fact that
most organic solvents, in essence, can be dissolved in supercritical
CO2. As supercritical CO2 is mixed with organic solvents containing
drug compounds, the solvent “expands” into the
supercritical CO2 effectively increasing the concentration
of the solute in the solution making it supersaturated and
causing the solute to precipitate or crystallize out of solution.
The precipitate can then be separated from the solvent/supercritical
CO2 mixture for packaging. The solvent/supercritical
CO2 mixture is next partially depressurized allowing facile
separation of the solvent from the now gaseous carbon dioxide.
This latter step allows for the recovery of all solvents used
in the process, and prevents venting of the solvent to the
atmosphere.
In practice, the procedure is more complicated.
The size of the droplet from which the drug is precipitated
and the propensity of the drug particles to agglomerate into
larger particles determine the ultimate size of the drug particle.
The former is dependent upon the droplet forming process which
is a function of the size of the droplet when created by atomization,
and the tendency of droplets to coalesce before precipitation
of the drug from the supersaturated droplet. The latter
is a function of the inherent and induced self-attractiveness
of the particles, which in turn is primarily determined by
surface properties of the particles themselves.
CritiTech uses ultrasonic energy produced
by a converging/diverging nozzle or an electromechanical oscillator
to shatter droplets into even finer droplets. This alone would
not enable the formation of submicron particles, as the droplets
have a tendency to immediately coalesce into larger drops.
In the CritiTech procedure, the drug-laden solvent is sprayed
into a flowing stream of supercritical CO2 which allows for
a rapid mass transfer of solvent into the stream of supercritical
CO2. This rapid mass transfer forces precipitation or crystallization
to occur prior to the coalescence of droplets. It is
this combination of techniques that allows CritiTech to produce
sub-micron particles of drugs or other chemicals.
Sub-micron Particles
A major application of CritiTech’s
core technology is the production of GMP grade pharmaceuticals
in sub-micron or nanoparticulate form. The pharmaceutical
industry has exhibited substantial interest in the availability
of processes to produce nanoparticulate drugs primarily because
of the problem of limited bioavailability of poorly water-soluble
compounds. By some estimates as many as 40% of all compounds
considered for formulation as drugs have such limited water
solubility as to make their use as drugs impossible.
The process of producing nanoparticulate
drugs begins with a research contract to determine the conditions
under which the client’s drug can be manufactured as
nanoparticles. The client will provide the drug in bulk
form along with sufficient information to identify a suitable
solvent for the drug. CritiTech will use this material
and information to produce test batches of the client’s
drug as nanoparticulate material. The nanoparticulate
material is returned to the client for bioavailability and
other testing and in an iterative process an optimal formulation
is developed.
At this stage, a second contract would
be negotiated to produce adequate amounts of the nanoparticulate
drug under GMP conditions to perform Phase I and/or Phase
II clinical trials. If these trials were successful,
production would then be scaled up to produce amounts adequate
for phase III clinical trials. Finally, if NDA approval is
obtained, a contract for manufacture of the commercial product
could be negotiated.
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