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 to manufacture the commercial product could be negotiated.

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