Nanoparticle Reactor Technology Controls Particle Size and Distribution

MJR PharmJet’s MicroJet Reactor technology won the 2017 CPhI Pharma Award for Excellence in Pharma: Manufacturing Technology and Equipment. Pharmaceutical Technology spoke with Emre Türeli, CEO of MJR PharmJet, about this technology.

PharmTech: What are the applications of nano- and microparticle formulations in pharma?

Türeli (MJR PharmJet): Nano- and microparticle formulations have many applications in pharma. They can be used for controlled drug delivery, increased activity, drug targeting, or increased dissolution for pulmonary formulations, for example. In parenteral formulations, nano- and microparticle systems can be used to increase the stability of an API in ready-to-use formulations, decrease the required injection volume, and enable formulation of low water-soluble drugs without the need for solubilizers. Furthermore, a classical application of parenteral micro- and nanoparticles is in the development of extended-release systems that provide drug release over months. Micro- or nanoparticle-based drug formulations are able to overcome one of the biggest challenges in drug development and drug delivery for oral formulations: water insolubility of pharmaceutical APIs. Creating API-specific nanoparticles increases in the dissolution rate of the API. This parameter influences the absorption, bioavailability, and onset of action of the API, all of which are important considerations in the development of oral and parenteral drugs.

PharmTech: How does MJR technology differ from traditional methods of forming nanoparticles?

Türeli (MJR PharmJet): MJR is a mixing chamber with advantages compared to conventional microchannel reactors. Two liquid streams are delivered through nozzles with sizes between 50–1200 µm, forming impinging jets that meet in the middle of the reactor, where a quick and efficient mixing takes place. The reactor room is filled with nitrogen for an efficient mixing that enables the control of particle properties, such as particle size and size distribution. The actual mixing process takes place in the reactor core, away from micro-sized channels, which eliminates the possibility of clogging in contrast to conventional microchannel reactors. MJR technology can be used for the production of emulsions, liposomes, solid lipid nanoparticles, inorganic nanoparticles, naked API nanoparticles, polymeric nanoparticles, and extended-release nanoparticles.

API-specific nanoparticles can be produced in two ways: top down, by a milling process or bottom-up, by a continuous precipitation process. Using MJR technology, API-specific nanoparticles are produced by continuous precipitation, based on a solvent anti-solvent precipitation; the precipitation is a direct formation of API-specific nanoparticles, without any milling process and thus, does not expose the API to any thermal or mechanical stress. In contrast, the widely used milling technology produces a lot of heat and mechanical stress, which is a limiting factor for many substance classes. Furthermore, the milling process is an iterative process where you have to change the hardware depending on batch size, and it is time consuming and costly.  

MJR technology is a GMP-compliant technology platform where the same setup is used for development and manufacturing purposes; no classical scale up is necessary during the technology transfer studies. Using the same equipment, production volumes from 10 mL/min up to 2000 mL/min can be realized. The same equipment is used in lab for development purposes and also in manufacturing facilities to produce the nanoparticles under GMP regulations. This advantage allows us to go directly from laboratory scale to commercial scale. The batch size of the commercial scale is only controlled through the production time.

MJR PharmJet works with its partner Leon-nanodrugs GmbH, who is the owner of the exclusive license of the MJR technology for the development and manufacturing of pharmaceutical nanoparticles used in end formulations.

PharmTech: How does the MJR process allow control of particle size and particle size distribution?

Türeli (MJR PharmJet): In the case of milling, one starts with microparticles and decreases the particle size with milling over time. In our case, because we have a bottom-up method, we directly produce the nanoparticles from a solution spontaneously once the solvent and non-solvent are mixed. Particle size and particle size distribution are controlled with variation of production parameters such as MJR nozzle size, flow rate, temperature, and pressure. Particle size can be adjusted to a desired value with the right combination of these parameters within the range of 30 nm up to several micrometers. The combination of the nozzle size and flow rate determines the mixing velocity of the two phases, which affects the particle size. The mixing time of solvent and non-solvent can be controlled by the flow rates of solvent and non-solvent. If the flow rate is increased, the velocity of the impinging jets are also increased, in which case they meet with a higher pressure in the MJR, resulting in shorter mixing times. Shorter mixing times of the solvent and the non-solvent in the reactor create smaller particles. [On the other hand,] an increase in the temperature results in an increase in the particle size by supplying additional energy into the system. The particle size is measured during the particle production using process analytical technology, and production parameters are automatically adjusted to achieve the desired particle size and particle size distribution.

MJR technology enables the production of homogenous particles with a narrow particle size distribution because it is a continuous production technology, in which the particle size is not affected by the batch size, but is controlled throughout production.

PharmTech: What are the keys to using quality by design (QbD) to optimize particle size?

Türeli (MJR PharmJet): There are two QbD approaches that can be used to optimize the particle size. The first one is the evaluation of formulation parameters. These parameters are solvent, API concentration, excipient selection, and excipient concentrations. These parameters can be varied with a design of experiments set up to determine the effects of parameters on particle size. Generally, larger particle sizes are achieved by increasing the API concentration and decreasing the miscibility of the solvent with the non-solvent system. Higher excipient concentration, on the other hand, results in smaller particle sizes.

Particle size can also be optimized through production parameters of the MJR setup. These parameters are flow rate, mixing ratio, temperature, and pressure. A variety of particle sizes can be achieved by variation of these parameters. All these parameters can be tested in a design of experiments setup with parameter limits derived from the development phase. Such a setup will result in optimum process parameters for the production of the particles with a desired particle size and particle distribution.