# US 7,744,923 B2 · Method for precipitation of small medicament particles into use containers

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- Number: US 7,744,923 B2
- Document ID: US7744923B2
- Status: Granted
- Kind: B2
- Application number: 11/870,554
- Filed: 2007-10-11
- Published: 2008-04-17
- Granted: 2010-06-29
- Earliest claimed: 2006-10-11
- Assignees: Crititech, Inc.
- Inventors: Roger A. Rajewski; Bala Subramaniam; Fenghui Niu
- Web page: https://patentgrep.com/patent/US7744923B2

## CPC

- A61K 9/1688: {resulting in pure drug agglomerate optionally containing up to 5% of excipient}
- B01J 2/02: by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
- B01J 2/04: in a gaseous medium {(if combined with suspending the material in a gas, e.g. fluidised beds B01J2/16)}
- B01J 2/18: using a vibrating apparatus
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

Commercially feasible methods for lyophobic precipitation of liquid-dispersed or dissolved material (e.g., medicaments) are provided wherein a plurality of individual, open containers (22) each containing a quantity (84) of a solution or dispersion are treated within a common pressurizable chamber (12). In this process, desired near-supercritical or supercritical temperature and pressure conditions are established for a selected antisolvent gas such as carbon dioxide, and an ultrasonic device (14) is actuated to generate high energy ultrasonic waves in the chamber (12). This leads to intense mixing of the antisolvent with the liquid solution or dispersion within the containers (22), with consequent solvent removal and material precipitation.

## Claims

### Claim 1

A method of simultaneous precipitation of material within a plurality of containers using an antisolvent gas, said method comprising:
locating a plurality of containers within a pressurizable chamber, each container being at least partially open to the atmosphere within the chamber and having a quantity of a liquid therein containing material to be precipitated;
heating and pressurizing said chamber with said containers therein;
introducing an antisolvent gas into the chamber and establishing temperature and pressure conditions within said chamber that are at near-supercritical or supercritical conditions for said antisolvent gas thereby forming near-supercritical or supercritical, respectively, antisolvent;
then with an ultrasonic device remote from the liquid containing material to be precipitated, generating ultrasonic energy waves within said near-supercritical or supercritical antisolvent in said chamber and propagating said waves through said near-supercritical or supercritical antisolvent in the interior of said chamber and into said containers, in order to mix said liquid and said near-supercritical or supercritical antisolvent, supersaturate the liquid with the material to be precipitated, dissolve the liquid in the near-supercritical or supercritical antisolvent, and precipitate the material as particles in said containers; and
removing said near-supercritical or supercritical antisolvent and liquid from said chamber and said containers, thereby leaving said particles in said containers.

### Claim 2 (depends on 1)

The method of claim 1, wherein each of said containers has a stopper loosely fitted within a mouth thereof during said removing, said method further comprising sealing each of said containers by fully installing each of said stoppers into said container mouths, after said removing.

### Claim 3 (depends on 1)

The method of claim 1, further comprising flowing additional near-supercritical or supercritical antisolvent through the chamber after precipitation of the material as particles in said containers.

### Claim 4 (depends on 1)

The method of claim 1, wherein said near-supercritical or supercritical conditions include a temperature of about 0.7-1.4 Tc and a pressure of 0.2-7 Pc for said antisolvent.

### Claim 5 (depends on 4)

The method of claim 4, wherein said material comprises a medicament.

### Claim 6 (depends on 1)

The method of claim 1, wherein said antisolvents is selected from the group consisting of carbon dioxide, propane, butane, ethane, isobutane, nitrous oxide, sulfur hexafluoride, trifluoromethane, xenon, and mixtures thereof.

### Claim 7 (depends on 1)

The method of claim 1, further comprising reducing the pressure within said chamber to approximately atmospheric after removing said liquid from said containers.

### Claim 8 (depends on 1)

The method of claim 1, wherein said supercritical or near-supercriticial conditions are maintained so as to prevent any substantial overflow of material from said containers during said removing.

### Claim 9 (depends on 1)

The method of claim 1, wherein said particles have an average diameter of 0.1-10 μm.

### Claim 10 (depends on 9)

The method of claim 9, wherein said average diameter is up to 0.6 μm.

### Claim 11 (depends on 1)

The method of claim 1, wherein said material comprises a medicament.

### Claim 12 (depends on 1)

The method of claim 1, wherein said material comprises at least 5% by weight of said liquid.

### Claim 13 (depends on 1)

The method of claim 1, wherein said material comprises at least 50% by weight of said liquid.

### Claim 14 (depends on 2)

The method of claim 2, further comprising flushing the containers with a fluid or inert gas after said removing and before said sealing.

### Claim 15 (depends on 14)

The method of claim 14, wherein the flushing is conducted for a period of 60-90minutes.

### Claim 16 (depends on 1)

The method of claim 1, wherein said material is a medicament, and said liquid comprises an auxiliary ingredient selected from the group consisting of adjuvants, excipients, extenders, surface active agents, binders and a combination thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein said auxiliary ingredient precipitates in said particles with said medicament.

### Claim 18 (depends on 1)

The method of claim 1, wherein said supercritical conditions include a temperature of 0.7-1.4 Tc and a pressure of 0.2-7 Pc for said antisolvent.

### Claim 19 (depends on 18)

The method of claim 18 further comprising flowing additional near-supercritical or supercritical antisolvent through the chamber after precipitation of the material as particles in said containers.

### Claim 20 (depends on 19)

The method of claim 19 further comprising flushing the chamber with a fluid or inert gas following said removing.

### Claim 21 (depends on 20)

The method of claim 20 further comprising reducing the pressure within said chamber to approximately atmospheric after said removing.

### Claim 22 (depends on 18)

The method of claim 18, wherein said material comprises a medicament.

### Claim 23 (depends on 22)

The method of claim 22, wherein said liquid further comprises an auxiliary ingredient selected from the group consisting of adjuvant, excipient, extender, surface active agent, binder and a combination thereof.

### Claim 24 (depends on 18)

The method of claim 18, wherein said antisolvent is selected from the group consisting of carbon dioxide, propane, butane, ethane, isobutane, nitrous oxide, sulfur hexafluoride, trifluoromethane, xenon, and mixtures thereof.

### Claim 25 (depends on 18)

The method of claim 18, wherein said particles have an average diameter of about 0.1-10 μm.

### Claim 26 (depends on 18)

The method of claim 18, wherein said material comprises at least 5% by weight of said liquid.

### Claim 27 (depends on 18)

The method of claim 18, wherein each of said containers has a stopper loosely fitted within a mouth thereof during said removing, said method further comprising sealing each of said containers by installing each of said stoppers into said container mouths after said removing.

### Claim 28

A method for the simultaneous formation of particles within plural containers, the method comprising:
locating plural containers within a pressurizable chamber, each container being at least partially open to the atmosphere within the chamber and having a quantity of a liquid therein, said liquid comprising liquid carrier and material to be precipitated;
heating and pressurizing said chamber;
introducing an antisolvent for the material into the chamber and establishing temperature and pressure conditions within said chamber that are at near-supercritical or supercritical conditions for said antisolvent thereby forming supercritical antisolvent, wherein said supercritical conditions include a temperature of 0.7-1.4 Tc and a pressure of 0.2-7 Pc for said antisolvent;
with an ultrasonic device remote from the liquid containing material to be separated, generating ultrasonic energy waves within said near-supercritical or supercritical antisolvent in said chamber and propagating said waves through said near-supercritical or supercritical antisolvent in the interior of said chamber and into said containers thereby mixing said liquid and said supercritical antisolvent, supersaturating the liquid with the material to be separated, dissolving the liquid in the supercritical antisolvent, and precipitating the material as particles in said containers;
flowing additional supercritical antisolvent through the chamber after precipitation of the material as particles in said containers;
removing said antisolvent and liquid from said chamber and said containers, thereby leaving said particles in said containers; and
reducing the pressure within said chamber to approximately atmospheric after said removing.

### Claim 29 (depends on 28)

The method of claim 28 further comprising flushing the chamber with a fluid or inert gas following said removing.

### Claim 30 (depends on 28)

The method of claim 28, wherein said material comprises a medicament.

### Claim 31 (depends on 30)

The method of claim 30, wherein said liquid further comprises an auxiliary ingredient selected from the group consisting of adjuvant, excipient, extender, surface active agent, binder and a combination thereof.

### Claim 32 (depends on 28)

The method of claim 28, wherein said antisolvent is selected from the group consisting of carbon dioxide, propane, butane, ethane, isobutane, nitrous oxide, sulfur hexafluoride, trifluoromethane, xenon, and mixtures thereof.

### Claim 33 (depends on 28)

The method of claim 28, wherein said material comprises at least 5% by weight of said liquid.

### Claim 34 (depends on 28)

The method of claim 28, wherein said particles have an average diameter of about 0.1-10 μm.