Dry powder formation using a variably constrained, divided pathway for mixing fluid streams

Active Publication Date: 2019-02-07
KELSIE BIOTECH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is a method for making a dry powder by delivering a liquid solution or suspension and an immiscible supercritical or near critical fluid to a flow path, which includes two or more flow passages of different diameters, at least one flow divider which divides and diverts the flowing mixture into at least two separate passages, wherein the separate passages subsequently intersect to combine their respective flows into a single flowing stream, rapidly reducing the pressure of the single flowing stream to form droplets, and then passing the droplets through a flow of inert drying gas to form a dry powder.

Problems solved by technology

Initially, drying technologies served only as crude micronization and solvent-removal methods, and lacked versatility.
Particle morphology, described by such characteristics as size, shape, internal and exterior structure, and surface properties, is difficult to intentionally design using an empirical approach because of the sheer number of variables involved in the drying process (Vehring 2007).
Decreasing the feed solution concentration is often an unattractive option, particularly when scale-up efforts are considered, as it leads to lower product yields during a given timeframe.
As solvent is progressively removed from the droplet, a shell begins to form at the droplet surface that impedes further reductions in size of the outer diameter.
Further solvent evaporation then occurs from near the center of the droplet, causing structural instability that results in buckling of the sphere or complete crumpling.
Removal of the blowing agent after the particle is dry results in the creation of pores of empty space as the blowing agent evolves from the dried particle matrix.
Although incorporation of certain excipients into the formulation can dispose the droplet drying process to form particles of low density, in many cases it is impractical or undesirable to allow the composition of the powder to be dictated by the necessary inclusion of these additives.
Sacrifices of drug concentration within a particle for the sake of improved aerodynamic properties may be untenable in many situations.
Additionally, in the case of respirable drug delivery, each additional excipient must be thoroughly tested for toxicity when inhaled into the lungs, an expensive and time-consuming process.
In addition to contributing to the dilution of active ingredients, the presence of additives that are necessary to obtain desired respirable fractions may be detrimental to the storage stability of the powder.
Particles composed of mixed states, such as partially crystalline or a mixture of polymorphs, exhibit reduced stability due to spontaneous nucleation and growth of the more stable crystalline polymorph.
Crystallization during storage of amorphous fractions of a particle often leads to water expulsion and plasticization of the powder (Vehring 2007).
Potential incompatibilities among neighboring physical states within the particle increase as the complexity of the formulation increases: the potential for components that spray-dry in crystalline form to negatively impact other components that spray-dry in an amorphous form is higher when the number of additives is large.

Method used

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  • Dry powder formation using a variably constrained, divided pathway for mixing fluid streams
  • Dry powder formation using a variably constrained, divided pathway for mixing fluid streams
  • Dry powder formation using a variably constrained, divided pathway for mixing fluid streams

Examples

Experimental program
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example 1

[0059]Mixing of equal volumes of two liquids according to the invention as described herein was modelled by CFD using the Solidworks® software.

[0060]The simulated liquid was methanol and the simulated immiscible fluid was supercritical or near critical carbon dioxide. The parameters were as follows: a first inlet was simulated to flow 1.5×10−5 m3 / s of methanol at a uniform flow rate. A second inlet was simulated to flow 1.5×10−5 m3 / s of liquid carbon dioxide at a uniform flow rate. The outlet was set to conditions of 101325 Pa and 293.2 K.

[0061]The results of the simulation are depicted schematically in FIG. 10B. The two streams (dark grey) were mixed nearly completely (mid-scale grey) by the time the flow stream reached the opening of the nozzle. The quantitative results of the simulation are shown in FIG. 11. The mass fraction of methanol approaches a value of 0.5 throughout the entire expanse of the lateral cross section of the nozzle opening, demonstrating thorough mixing of the...

example 2

[0062]Dry inhalable powder according to the invention was prepared as described herein.

[0063]A methanol / water solution (7:3 methanol:water) comprising 16% w / w total dissolved solids was made. The dissolved solids were composed of 90% w / w mannitol and 10% methionine. The solution was divided in half and dried using the previously described CAN-BD process with the following parameters: 2.0 ml / min. carbon dioxide flow rate, 1.0 ml / min. solution flow rate, 40° C. nitrogen drying gas temperature, 40 L / min. nitrogen drying gas flow rate, 75 μm internal diameter fused silica restrictor, 5 cm long fused silica restrictor, and 0.45 μm Nylon powder-collection filter. One half of the solution was dried with the typical CAN-BD low-volume tee nozzle schematically depicted in FIG. 4, and the other half of the solution was dried with an improved nozzle design according to the invention, as shown in FIG. 12.

[0064]The dimensions of the improved nozzle in this example were as follows. The 0.35 mm ori...

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Abstract

Methods of making a dry powder, comprise (a) delivering a liquid solution or suspension and a second, immiscible fluid to a flow path, (b) transporting the liquid solution or suspension and the immiscible fluid along the flow path, wherein the flow path includes two or more flow passages of different diameters, at least one flow divider which divides and diverts the flowing mixture into at least two separate passages, wherein the separate passages subsequently intersect to combine their respective flows into a single flowing stream, (c) rapidly reducing the pressure of the single flowing stream, whereby droplets are formed, and (d) passing the droplets through a flow of inert drying gas to form a dry powder. A nebulizing nozzle includes an inlet, a flow path as described, and a restrictor nozzle outlet.

Description

FIELD OF THE INVENTION[0001]The present invention is directed to methods of making a dry powder by mixing a liquid solution or suspension and an immiscible supercritical or near critical fluid and transporting the liquid solution or suspension and the immiscible fluid through a defined flow path and a nebulizing nozzle. In the defined flow path, the liquid solution or suspension and the immiscible supercritical or near critical fluid are thoroughly mixed through a sequential variation in flow path diameter and a division and reunification of the flow path. A fine emulsion or solution exits the nozzle is dried under a stream of inert drying gas to produce a dry powder.BACKGROUND OF THE INVENTION[0002]Dry powder preparations are used ubiquitously throughout the pharmaceutical, nutraceutical, biotechnological and food industries. Particle engineering often incorporates elements from microbiology, chemistry, formulation science, colloid and interface science, heat and mass transfer, sol...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K38/28B01J2/04B01F23/00
CPCA61K9/0075A61K38/28B01F2003/0064A61M2202/064B01J2/04A61K9/1694B01F23/043
InventorGILDELAMADRID, XUNOSIEVERS, ROBERT E.
OwnerKELSIE BIOTECH LLC