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The LaminarPace Micronizing technology

“Introducing the LaminarPace Micronizing Technology for the formulation of very small amounts of small and macro molecules in high yields at room temperature”

Executive Summary

• Facilitates the early testing of drug candidates in different assays, including inhalation tests, by formulating 100mg batches of a compound into micron-size powders in high yields at room temperature.
• Increases the dissolution rate by finely dividing coarse materials into fine powders of micrometer-size particles (micronization)
• With a typical production speed of 20-100 mg dry substance/hour, up to 1g of a compound can be formulated per day at a product yield of > 90% for batches down to 20mg.
• Operating temperature: ambient
• Solvent residues: Removes >98% of solvent vapors before collection of product particles.

Background

Early on in the drug development process small amounts of new substance are synthesized and obtained in small solvent fractions from purifier columns. Attempts are then made to crystallize the substance in as pure crystals as possible, usually characterized by larger regular crystals. Quite often only oily residues of inferior quality can be obtained, which at this point is most often not further used.

Problem

After synthesis, the crystalline product is to be used for further testing. A small amount of substance in the form of amorphous residues or larger crystals is now an impractical form to use; i) minute subfractions are difficult to obtain with accuracy, ii) the dissolution rate of larger crystals can be very slow making the substance hard to use where further testing is to be done with the dissolved substance, and iii) inhalation testing with neat substance is impossible without having the substance in a form where all particles are < 5 µm.

Solution

The obvious solution is to finely divide the crystals into a more volumeous powder of micrometer-size crystals (micronization), and a number of methods are available including spray-drying and milling.

Market need

However, the commercially available techniques are intended for use with substance amounts in the range of a gram and upwards.

There is currently no practical method to formulate/micronize powders from crystals in the range up to 100 mg with a high degree of efficiency at room temperature.

There is a need for a micronization technology to enable production of very small amounts of pharmaceutical compounds in high yields at room temperature.

Product Presentation

The LaminarPace spray dryer was developed to obtain a process where 100mg batches of substance can be formulated into micron-size powders with an efficiency of >90%. The particle size distribution is most often very narrow around the median diameter.

The uniqueness of the process stems from the fact that the solvent is completely stripped from the product stream before particle separation instead of driving the solvent off the particles to the surrounding air by increasing the temperature as with conventional spray dryers. The low flow rate in the system provides a laminar flow field that render losses to the vessel walls close to negligible.

Powders are spray dried at room temperature, so even small batches of thermolabile proteins and peptides can be produced with retained biological activity, and once radiolabelled substance is available, micronized powder of desired specific activity can be easily produced. Substances can also be dried from organic solvents without any risks of vapour explosions.

The LaminarPace technique can be used to formulate mg amounts of substance into powders in small batches both to (1) facilitate the early testing of drug candidates in different assays in general, and to (2) provide powders to be used directly for inhalation exposures to inhalable aerosols with the DustGun Technology.

Target Group

Pharmaceutical companies. Early development/discovery in chemistry and preclinical departments (pharmacology/toxicology).

Spray Dryer Tentative Product Profile

• Facilitates the early testing of drug candidates in different assays, including inhalation tests, by formulating 100mg batches of a compound into micron-size powders in high yields at room temperature.
• Increases the dissolution rate by finely dividing crystals into volumeous powder of micrometer-size crystals (micronization).

A brief comparison with other technologies

Compared to other principles for formulation/micronization of soluble compounds the LaminarPace technology differs in the following way:

Conventional spray drying

The solvent is driven off the particles to the surrounding air by increasing the temperature. Consequently, this may cause problems with compound stability. The high process flow rate leads to a poor recovery of the compounds. With the LaminarPace technology the solvent is completely removed from the particle stream (>99%) and the low flow velocity of the process gives high product yields.

Supercritical spray drying

This technology uses solvent mixtures and high pressures, which makes the process difficult to control. As a result, when smaller amounts of substance are processed the product yield is often very low. The LaminarPace technology, on the other hand, is easy to control, which is done under full control of all operating parameters with a LabView application developed for the purpose.

Freeze drying

Compared to freeze drying of small batches of a compound the LaminarPace technology is considerably faster and generates a much finer powder which is easier to handle and to dissolve.

Milling

The LaminarPace technology is much more lenient and because of smaller losses to the vessel walls, it generates far better yields when processing smaller amounts of substance.

The LaminarPace technology is quite unique on the market when minute amounts of expensive substance are to be formulated in high yields for convenient further use. The technology is also well suited for formulating radiolabelled compounds.

Process characteristics

With a typical production speed of 20-100 mg dry substance/hour, up to 1g of a compound can be formulated per day at a product yield of > 90% for batches down to 20mg.

Typical particle size distribution:	1-5μm
Example: 5% cromolyn: Mass Median Diameter: 3.5µm Geometric Standard Deviation:<1.9
Overall particle yield:	90% (i)
Concentration of substance:	1-10% (in spray solution by weight)
Operating temperature:	ambient
Solvents:	H20; alcohol (≤100%); hexane (≤100%),
Solvent residues:	Removes >98% of solvent vapors before collection of product particles.
Crystallinity of powder:	generally higher compared to conventional technologies

(i) Performance is measured as the yield of powder collected in a delivery vial as a fraction of the weight of substance added