Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/05—Stirrers
  • B01F27/051—Stirrers characterised by their elements, materials or mechanical properties
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/05—Stirrers
  • B01F27/051—Stirrers characterised by their elements, materials or mechanical properties
  • B01F27/053—Stirrers characterised by their elements, materials or mechanical properties characterised by their materials
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/05—Stirrers
  • B01F27/07—Stirrers characterised by their mounting on the shaft
  • B01F27/071—Fixing of the stirrer to the shaft
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/05—Stirrers
  • B01F27/09—Stirrers characterised by the mounting of the stirrers with respect to the receptacle
  • B01F27/091—Stirrers characterised by the mounting of the stirrers with respect to the receptacle with elements co-operating with receptacle wall or bottom, e.g. for scraping the receptacle wall
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/05—Stirrers
  • B01F27/11—Stirrers characterised by the configuration of the stirrers
  • B01F27/118—Stirrers in the form of brushes, sieves, grids, chains or springs
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
  • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
  • B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials

Definitions

• the present invention relates to the field of dissolution measurement and, more particularly, to a low-speed precision stirring/mixing device for repeatable dissolution of solid or granular material.
• a solid oral pharmaceutical product such as a tablet or capsule, is generally composed of a mixture of active ingredient(s) and excipient (i.e., pharmacologically inactive ingredients compressed into a desired shape).
• excipient i.e., pharmacologically inactive ingredients compressed into a desired shape.
• the active ingredient When the product is administered to a patient, it is expected that the active ingredient will be released into the gastrointestinal (GI) tract in a predictable and reproducible manner which, in turn, is absorbed into systemic circulation to elicit the desired effect.
• GI gastrointestinal
• There are a number of factors such as: nature and composition of active and inactive ingredients, manufacturing process, and/or storage conditions which can alter the drug release characteristics of a product, and consequently the outcome in a patient.
• bio-availability and/or bio-equivalence study also commonly termed as a bio-study.
• a drug product is administered to human volunteers and a number of blood samples are withdrawn at different time intervals.
• these blood samples are then analyzed to determine the drug levels.
• the resulting blood concentration-time profiles form the basis of bio- availability and bio-equivalence assessment.
• Cmax highest observed concentration
• aqueous dissolution medium water or buffers
• the logic behind assessing the drug release in water or aqueous buffer solution is that, if a drug is to be absorbed from the GI tract into the systemic circulation, the drug has to be in a solution form.
• any changes in drug release characteristics in solution should, at least in theory, be reflected in corresponding changes in drug availability in systemic circulation.
• the paddle apparatus is the most commonly used.
• the paddle apparatus provides a mixing vessel 2 (which is typically round-bottomed) into which an aqueous medium 4 is placed. Stirring of the aqueous medium 4 is achieved by means of a T-shaped paddle 6 which is supported within the vessel and rotated by a motor-driven spindle (not shown).
• a typical paddle apparatus normally has six or twelve dissolution vessels 2, to enable simultaneous testing of multiple samples.
• a product tablette
• the stirring/mixing is achieved by rotating the paddle 6 at a desired speed, typically 50- 100 rpm.
• a limitation of the conventional paddle apparatus is that the rotating paddle 6 creates a vortex effect, allowing the disintegrated (powdered) product 8 to accumulate at the bottom of the vessel 2. This reduces the available surface area of solid particles, reducing interaction between these particles and the dissolution medium, which leads to artificially low dissolution rates. This can cause the current methodology to provide inaccurate and non-repeatable estimates of drug release rates.
• Low speed mixing devices are known in non-analogous arts, such as dough making. Examples of such devices are shown in Canadian Patents No. 1,052,766 to Kramer and No. 1,038,858 to Smader, in which a kneading arm has a shape that conforms approximately to the bottom shape of the mixing vessel. However, this arm is the only active part in the mixing of the material, and is designed for high torque mixing to provide a high shearing effect to force the material together. Lumps and irregularities in cohesive material are broken by high shearing forces within the dough. This can be efficient with highly cohesive material (such as flour and water), but will leave material at the bottom of the mixing vessel in any other situation.
• highly cohesive material such as flour and water
• United States Patent No. 4,197,018 to Groen discloses a mixer for a cooking vessel in which an arm follows closely the shape of the bottom part of the vessel. The principal effect of this arm is to scrape the bottom of the vessel. A stirring blade pushes the material around. This is only useful in a context of floating material and to prevent any material from sticking to the vessel. The combined surface of the arm and of the stirring blade is far too large for an efficient mixing of material, and is designed more to push the material around the vessel so that it will not stick to the vessel.
• United States patent No. 5,908,241 discloses a variation on the preceding devices, in which brushes are replaced by a helical open coil for mixing. This device also relies on the high shear fluid flow effects to mix/break the material.
• the present invention provides a low-speed precision stirring/mixing device for dissolution of solid or granular material for use in measuring the release characteristics of an active ingredient in a pharmaceutical product.
• an aspect of the present invention provides a mixing device for low speed precision mixing of contents of a vessel.
• the mixing device comprises a support member adapted to be rotatably supported in spaced relationship from a bottom portion of the vessel and separated therefrom by a gap; and a brush assembly depending from the support member for sliding engagement with the bottom portion of the vessel. Low speed rotation of the support member within the vessel causes the brush assembly to sweep the bottom portion of the vessel while mixing the contents of the vessel.
• the brush assembly comprises a resilient coil or a plurality of filamentary or lamellar elements, affixed to the support member.
• FIG. 1 is a sectional view of a prior art paddle mixing apparatus
• FIG. 2 is a sectional view of a mixing device in accordance with a first embodiment of the present invention
• FIG. 3 is a sectional view of the mixing device of FIG. 2, including a coupler and resilient pressure member;
• FIG. 4 is a sectional view of a mixing device in accordance with a second embodiment of the invention.
• FIG. 5 is a sectional view of a mixing device in accordance with a third embodiment of the invention.
• FIG. 6 is a sectional view of a mixing device in accordance with a fourth embodiment of the invention.
• FIG. 7 is a sectional view of a mixing device in accordance with a fifth embodiment of the invention.
• FIG. 8 is a graph showing exemplary comparative dissolution profiles obtained using the prior art paddle mixer and the mixing device of FIGs 2 and 3.
• the present invention provides a mixing device for low speed precision mixing of contents of a vessel.
• precision mixing shall be understood to mean that the contents of a vessel are mixed in a controlled and repeatable manner.
• the present invention is particularly suited for use in a dissolution measurement apparatus, where repeatable dissolution and mixing are highly important, and especially as a replacement for the paddle type agitator commonly used.
• Various embodiments of the present invention are described below with reference to FIGs. 2-7.
• the mixing device 10 generally comprises a support member 12, and a brush assembly 14 mounted on the support member 12.
• the support member 12 is designed to be rotatably supported in a conventional dissolution vessel 2 containing a dissolution medium 4.
• the support member 12 at least approximately conforms to the shape of a bottom portion of the dissolution vessel 2 and is separated therefrom by a gap 16.
• a substantially uniform gap 16 is beneficial, in that it simplifies the design of the brush assembly 14, but it is not necessary.
• the brush assembly 14 can be mounted on the support member 12 by any suitable means, and fills the gap 16 so as to enter into sliding engagement with the bottom of the vessel 2.
• the brash assembly 14 comprises a plurality of filamentary elements that extend substantially perpendicularly to the support member.
• the support member 14 is designed to be coupled to a suitable drive system, such as, for example, a conventional motor-driven spindle (not shown) which imparts a low speed rotation to the support member 12, causing the brush assembly 14 to gently sweep the bottom portion of the dissolution vessel 2.
• a suitable drive system such as, for example, a conventional motor-driven spindle (not shown) which imparts a low speed rotation to the support member 12, causing the brush assembly 14 to gently sweep the bottom portion of the dissolution vessel 2.
• the term "low-speed rotation” should be understood to refer to rotation speeds of about 100 rpm or slower, typically in the order of 50 rpm.
• the resulting low speed sweeping action of the brush assembly 14 minimizes accumulation of disintegrated (i.e., particulate) test product within the vessel 2, and provides substantially continuous low-shear interaction between the dissolution medium 4 and the pharmaceutical product.
• the support member 12 is preferably comparatively rigid, in order to enable secure coupling to the drive system (not shown) and controlled rotation of the support member 12 and brush assembly 14.
• the support member 12 may suitably be provided as two or more strands of wire twisted together, or a bar of flat or round material.
• the support member 12 is made of a food grade or other substantially biologically and/or chemically inert material.
• the brush assembly 14 is preferably also made of a food grade (or biologically and/or chemically inert) material such as stainless steel, TeflonTM or nylon.
• inert material shall be understood to refer to any material that is substantially non-reactive with the vessel or the contents to be mixed, so as to not interfere with the desired chemical or biological process taking place in the vessel.
• Typical materials usable for the purposes of the present invention include (but are not limited to) stainless steel, polytetrafluoroethylene (PTFE, e.g., TeflonTM) stainless steel coated with TeflonTM, polyamide polymer (e.g., nylon - trade name) or other food grade plastic.
• the vessel 2 shown has a curved, semi-spherical bottom, as in a standard dissolution test apparatus.
• the invention is in no way limited to such embodiments. Indeed, the brush assembly can readily be adapted to conform to the bottom of vessels having any desired profile.
• FIG. 3 shows the mixed device 10 of FIG. 2, in which a coupling 18 is used to couple the support member 12 to a drive unit (not shown) such as may be commonly used in a standard dissolution test apparatus.
• This coupling 18 can be made integral with an upper portion of the support member 12 or may be detachable, as desired.
• the coupling 18 includes a shaft 20 extending from the drive unit, and a resilient pressure member 22.
• the pressure member 22 is designed to resiliently bias the brush assembly 14 into contact with the bottom portion of the vessel 2.
• the pressure member 22 can be provided as a spring, or any other suitable resilient element, such as, for example, an elastomeric element.
• FIGs. 4, 5, 6 illustrate principle features of various alternative embodiments of the present invention.
• the brush assembly 14 is provided by a resilient coil affixed to, and surrounding the support member 12.
• the brush assembly 14 is provided by a resilient coil affixed to the support member 12 between the support member 12 and the bottom portion of the vessel 2.
• This embodiment also includes an alternate design of the support member 12, in which a stem 24 of the mixing device 10 extends from a central portion of the support member 12.
• FIG. 6 illustrates an embodiment of the present invention wherein the support member 12 is extended to form a closed loop coupled to the stem 24.
• FIG. 6 also illustrates an embodiment wherein the brash assembly 14 is provided by a plurality of lamellar elements affixed to the support member 12.
• filamentary elements and “lamellar elements” are intended to encompass these elements being affixed to the support member 12 at a single point (and having a free end), or at two or more points to, thereby form loops.
• FIG. 7 illustrates another embodiment of the present invention wherein the support member 12 does not conform to the contour of the bottom portion of the (now flat-bottomed) vessel 2.
• the brash assembly 14 is mounted on the support member 12, and is extended to bridge the unequal gap between the support member 12 and the bottom portion of the vessel 2.
• the brash assembly 12 enters into sliding engagement with the bottom portion of the vessel 2, in spite of the unequal gap.
• FIG. 8 is a graph illustrating exemplary comparative dissolution profiles of the prior art paddle mixer and a mixing device 10 in accordance with the present invention.
• drug release profiles of a commercially available 250 mg amoxicillin capsule product are described.
• the test product is a conventional release product i.e., fast-release drug product.
• Two sets of experiments were conducted using a 6-spindle dissolution apparatus with six identical dissolution vessels, each having 900 ml of dissolution medium, hi one experiment, each spindle drove a prior art paddle mixer. In the other experiment, each spindle drove a mixing device 10 in accordance with the present invention. In both experiments, the spindles were rotated at 50 rpm.
• the bottom curve represents the percentage dissolution versus time for the prior art paddle stirrer.
• the product is a fast-release product by rapidly releasing the content of capsule shell, in this case the drug's appearance in solution is delayed due to poor interaction of the dissolution medium (liquid) with the drug product using the paddle stirrer.
• the dissolution curve seems to imply that the test product is a slower release product than it actually is.
• the top curve represents the percentage dissolution versus time achieved using the present invention.
• the interaction of the dissolution medium with the product is enhanced using the present invention and the dissolution curve more accurately reflects dissolution characteristics of the fast drug release product.

Landscapes

• Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Mixers Of The Rotary Stirring Type (AREA)

Priority Applications (1)

Applications Claiming Priority (6)

Publications (1)

Family

ID=27171604

Family Applications (1)

Country Status (2)

Cited By (2)

Citations (6)

• 2002
  • 2002-09-25 WO PCT/CA2002/001452 patent/WO2003026784A1/en not_active Application Discontinuation
  • 2002-09-25 EP EP02764426A patent/EP1432505A1/de not_active Withdrawn

Patent Citations (6)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events