WO2007104766A1

WO2007104766A1 - A dissolution sample preparation apparatus and method with both mechanical and ultrasonic homogenisation

Info

Publication number: WO2007104766A1
Application number: PCT/EP2007/052370
Authority: WO
Inventors: Sean Scott; David Timothy Westmoreland
Original assignee: Astech Projects Limited
Priority date: 2006-03-15
Filing date: 2007-03-13
Publication date: 2007-09-20
Also published as: GB0605127D0; GB2436143A

Abstract

An apparatus is disclosed for processing multiple samples of a solid preparation to provide a set of solutions, each of which corresponds to one of the samples and contains dissolved active material extracted from it. The apparatus is particularly suited to processing of pharmaceutical samples, to ensure consistency of dosage etc. It comprises means for preparing a mixture containing one of the samples and a pre-determined quantity of solvent, and a mechanical homogeniser 67 arranged to act upon the mixture and to break down the solid preparation to form a particulate suspension of it in the solvent. In accordance with the invention, this suspension is also processed by an ultrasonic actuator, 90, 92 (preferably formed as a flow cell) which excites the suspension and promotes dissolution of the active material. The apparatus also comprises a multi-use filter which is backwashed between samples. A method of processing multiple samples is also disclosed.

Description

A DISSOLUTION SAMPLE PREPARATION APPARATUS AND METHOD WITH BOTH MECHANICAL AND ULTRASONIC HOMOGENISATION

The present invention is concerned with an apparatus and method for

processing a solid sample to produce a solution containing active

components of the sample. It is applicable particularly, but not

exclusively, to samples of pharmaceutical preparations.

In the pharmaceutical industry it is necessary to test preparations such as

tablets and powders to ensure consistency of the dosage of their active

ingredients. Other tests - e.g. for the presence of impurities - may also be

required. A first step in this process is to dissolve the preparations' active

ingredients in a known quantity of a solvent. The resulting solution is

then subject to the necessary tests. Large numbers of samples - e.g. of

tablets - must be individually tested, with a separate solution being

created from each. There are devices on the market which carry out the

process automatically on a batch of such samples. Robotic handling

systems are used to carry out the manipulation involved in repeatedly

preparing a solvent/sample mixture, breaking down the sample to release

its active ingredients, filtering the solution to remove particles of filler

material, and dosing the resultant solutions into individual containers. Some problems are encountered. The following are among them.

The temperature rise to which the sample can be subject is typically

specified and is small. Known devices use a mechanical homogeniser to

break down the sample and to promote dissolution of its active

ingredients, requiring a protracted homogenisation process. Heat is

imparted to the sample. It is desired to reduce such heating, and

additionally or alternatively to reduce the time required to dissolve the

active ingredients.

Contamination of one sample by another is to be avoided. To this end, the

known devices use disposable filters, a new filter being taken for each

sample processed. The automation of the process of filter replacement is

notoriously problematic.

In accordance with a first aspect of the present invention, there is an

apparatus for processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

apparatus comprising an arrangement for preparing a mixture containing

one of the samples and a predetermined quantity of solvent; a mechanical homogenJser which is arranged to act upon the mixture and to break

down the solid preparation to form a particulate suspension thereof in the

solvent; an ultrasonic actuator which is arranged to ultrasonically excite

the suspension and so to promote dissolution of the active material; and

an output arrangement for outputting the resulting solution to a sample

vessel.

In accordance with a second aspect of the present invention there is an

apparatus for processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

apparatus comprising an arrangement for preparing a mixture containing

one of the samples and a predetermined quantity of solvent; a dissolution

device for dissolving active components of the solid preparation in the

solvent; a filter and associated conduits and a pump for passing at least

some of the resulting fluid through the filter in a forward direction to

remove particulate material from it; and an output arrangement for

outputting the resulting solution to a sample vessel; the device being

characterised in that it further comprises valves and conduits for passing

cleaning fluid through the filter in a reverse direction, opposite to the

forward direction, to back wash the filter between processing of the

samples. In accordance with a third aspect of the present invention there is a

method of processing multiple samples of a solid preparation to provide a

set of solutions each of which corresponds to one of the samples and

contains dissolved active material extracted from it, the method

comprising preparing a mixture containing one of the samples and a

predetermined quantity of solvent; mechanically homogenising the

mixture to break down the solid preparation to foπn a particulate

suspension thereof in the solvent; ultrasonically exciting the suspension

and promoting dissolution of the active material; and outputting the

resulting solution to a sample vessel, these steps being repeated for each

sample.

It is particularly preferred that the method comprises dispensing a

required quantity of fluid by: dispensing a first metered dose of fluid,

which is smaller than the required quantity but is a large proportion of it;

weighing the first dose of fluid; calculating, based upon the weight of the

first dose, the additional quantity of fluid required to achieve the required

quantity; and dispensing the calculated additional quantity of fluid in a

second metered dose. In accordance with a fourth aspect of the present invention there is a

method of processing multiple samples of a solid preparation to provide a

set of solutions each of which corresponds to one of the samples and

contains dissolved active material extracted from it, the method

comprising preparing a mixture containing one of the samples and a

predetermined quantity of solvent; dissolving active ingredients of the

sample in the solvent; passing the solution produced by the ultrasonic

excitation step through a filter in a forward direction; outputting the

resulting solution to a sample vessel; and back washing the filter by

passing cleaning fluid through it in a reverse direction; these steps being

repeated for each sample.

It must be understood that the solid preparation being analysed may be

granular, and may in particular take the form of a powder.

Specific embodiments of the present invention will now be described, by

way of example only, with reference to the accompanying drawings, in

which :-

Figure 1 is a perspective view of an apparatus embodying the present

invention, viewed from the front, and with some parts of a casing cut

away to reveal interior components; Figure 2 is a perspective view of the same apparatus, viewed from one

side;

Figure 3 is a perspective view of a cover for the apparatus;

Figure 4 is a perspective view of a bowl feeder of the apparatus;

Figure 5 is a cut-away view of a hopper of the apparatus;

Figure 6 is a perspective view of a homogeniser of the apparatus;

Figure 7 is a perspective view of an ultrasonic flow cell of the apparatus;

Figure 8 is a perspective view of a filter of the apparatus and associated

stand;

Figure 9 is a schematic representation of fluid connections in the

apparatus; and

Figure 10 is a perspective view of a holding device of the apparatus. The illustrated apparatus 10 is used to process solid pharmaceutical

preparations. Typically these are tablets, but other forms of

pharmaceutical preparation, including powders, may also be processed.

The apparatus serves to extract from the solid preparation its active

pharmaceutical components and to place them in solution ready for

analysis. This is done in an automated and repeatable process, enabling

e.g. a batch of tablets each to be individually processed and analysed

without intervention by an operator.

The main components of the apparatus will firstly be described, and this

will be followed by an explanation of how the processing is carried out.

The apparatus typically receives a batch of tablets. Some form of feeder

device is needed to supply the tablets individually, or in groups of two or

more, for¹ processing. Various suitable devices will be known to the

skilled person and could be used in this context, but the illustrated

embodiment uses a bowl feeder 12 which is best seen in Figure 4. A

helical path 16 ascends to a delivery chute 18. Vibration of the helical

path causes the tablets to ascend along it and so to emerge one-by-one

from the chute 18. The bowl feeder is able to accommodate a range of

sizes of tablets. It may also be used to supply a controlled dose of a

preparation in powder form. Note that the feeder could be omitted altogether, the pharmaceutical

preparation then being manually dispensed.

The tablets are supplied to a hopper 20 which is most clearly seen in

Figure 5 and comprises an upper part 22 and a lower part 24. The upper

part 22 has at its base an upwardly convergent frusto-conical portion 25

whose upper extremity leads to a hollow stem 26. In its turn the stem 26

leads to a broader, cylindrical portion 28 which is upwardly open to

receive a test tube and has an exterior flange 30 to facilitate its

manipulation by a robotic device, to be described below. In Figure 5, the

upper part 22 of the hopper is supported upon a stand 32 comprising an

upright rod 34 which projects into the stem 26, an intermediate support

head 36 of the stand abutting the frusto-conical portion 24 to support the

weight of the hopper. The lower part 24 of the hopper has at its base a

cylindrical, downwardly open skirt 38 with an interior, inclined lip 40

which enables it to rest upon the neck of a mixing vessel 42 (which is

seen in Figure 1 and will be described below). An annular end wall 44 at

the top of the skirt leads to an upwardly divergent funnel portion 46. Note

that the lower part 24 of the hopper is, in Figure 5, suspended from the

upper part 22 by virtue of a short bevel 48 formed upon the funnel portion

46 which rests on the frusto-conical portion 24. Hence while the hopper 20 is supported through its upper part, as in Figure 5, the funnel portion

46 is downwardly closed. In use, the pharmaceutical preparation is

dispensed into the receptacle formed by the funnel portion 46 and is

initially retained in it. However when the hopper is supported through its

lower part 24, as when it is placed upon the mixing vessel 42, its upper

part 22 descends, opening the funnel portion to automatically release the

phannaceutical preparation through the funnel portion 46.

Note that that the hopper stand 32 is itself mounted upon an electronic

balance 48, to provide for weighing of the hopper's contents. It projects

upwards through an opening 49 in a deck of the apparatus, allowing the

balance 48 to be mounted beneath the deck. Also the hopper is multi¬

functional, serving as both a receptacle for the phannaceutical preparation

to be processed and as a test tube holder. In both roles it substitutes for a

balance pan, as will become clear below.

The apparatus further comprises a multi-functional handling robot. In the

illustrated embodiment this comprises a mechanical handling arm 50 and

a liquid handling arm 52 which are both mounted upon a support beam 54

and able to move along it. The handling robot is controlled by means of a

CPU mounted within the unit. A holding device 60 is carried upon and

movable along the mechanical handling arm 50. Figure 10 shows a pair of jaws 62 of the holding device which are movable toward / away from

each other so that items can be held and released, and the jaws have two

pairs of shaped inner pads 64, 66 to adapt them for holding (a) the neck of

the mixing vessel 42 and (b) a test tube 68 and (c) the hopper 20. Carried

upon and movable along the liquid handling arm 52 are a set of

dispensing tubes 66, whose function will be described below.

The apparatus further comprises a mechanical homogeniser 61 which acts

upon a combination of the pharmaceutical preparation and a solvent,

which may comprise a mixture of different solvent materials, presented to

it in the mixing vessel 42. The position of the homogeniser can be seen in

Figure 2 and its construction is most clearly depicted in Figure 6. It has a

stepped columnar part 68 whose larger diameter upper portion 70 houses

an induction type electric motor 56, mounted in a motor housing which is

chosen for its low heat output and (due to the lack of brushes) the low

risk that it will ignite any flammable air-borne material such as solvent

fumes. Button 58 serves as a homogeniser control switch. A shoulder

formed on the columnar part leads to a smaller diameter portion 72

insertable into the neck of the mixing vessel 42. The shoulder also carries

an elastomeric seal 73. Also the neck of the mixing vessel 42 is

accurately ground, to form an effective seal with the columnar part

against egress of material during homogenisation. Projecting downwardly from the columnar part 68 is a tube 74 with a castellated, open lower end

76 through which material is able to enter the tube 70 and so to contact a

rotary homogenising head within it. The head itself is not shown in the

drawings, but is of a type known to those skilled in the art and is driven

by the electric motor. Its action tends to draw in the fluid mixture through

the open end of the tube 70 and to expel it through radially facing

apertures 77. The homogeniser is unconventional in that it also comprises

a set of dispensing tubes 78 which are arranged to be supplied with fluid

and to dispense it through openings at intervals along their lengths. A

siphon tube 80 is also provided, for withdrawal of the homogenised

material. A spacer ring 82 maintains the relative positions of the

dispensing and siphon tubes 78, 80.

The mixture withdrawn from the mixing vessel comprises a finely

divided suspension of the pharmaceutical preparation in solvent. It is led

to an ultrasonic flow cell 84 in which it undergoes a dissolution step by

ultrasonic action. The flow cell is mounted within the apparatus and so is

not seen in Figure 1, but is depicted in Figure 7. Fluid conduits connected

to the inlet 86 and outlet 88 are omitted from this drawing, but it is to be

understood that the former is connectable with the siphon tube 80 and the

latter is connectable to a filter, to be described shortly. In the present

embodiment the flow cell is actuated by a piezoelectric device contained in a head 90 and coupled through a stem 92, which serves as a waveguide,

to the cell's fluid conduit 94. Liquid coolant is supplied to prevent

excessive heating of the material being processed. The coolant - winch in

the present embodiment is water - is chilled by means of a Peltier device

(which is not itself shown, but is of a type well known to those skilled in

the art). It enters a jacket around the fluid conduit 94 through a coolant

inlet 96 and leaves it through coolant outlet 98. Of course other types of

refrigeration device could be used in place of the Peltier device, if desired.

The dissolution step causes the active components of the pharmaceutical

preparation to be dissolved in the solvent, but particles of solid carrier

material remain. Particles above a chosen size threshold are removed by

means of filter 100, which is seen in Figures 1 and 8. A generally "C"

shaped filter stand 102 contains conduits (not shown) for supply of fluid

to the filter. It also allows for straightforward filter replacement, when

necessary. The filter element in the present embodiment is foπned of

PTFE and is of membrane type. Suitable elements are known in the trade

as "Millipore" filters. A pore size of 0.45 micron has been used in trials,

but of course this will be chosen according to the application. Other types

of filter element may be used. The filter is disposable, but according to

the present invention it can be used for multiple samples prior to

replacement, as will be explained below. The apparatus as a whole has what is referred to as a "clean deck" design

which assists in maintaining hygiene.. The deck, mechanisms and cover

106 are placed upon a chassis similar to that shown in Figure 1 , item 104.

This chassis will come in two forms: a low height version as shown in

Figure 1 , which will be suitable for mounting on a typical bench top or

table, or a taller version which will be suitable for placing directly onto

the floor. The tall version of the chassis will contain tanks for the

solvents and all associated piping. This tall version of the apparatus will

be totally self-contained. The bench top version will require solvent

tanks to be positioned hi close proximity to it.

The cover 106 will be peπnanently secured to the chassis. Access to the

process will be through doors in the cover. This cover is designed to

maintain operator safety by preventing operator access during the

operating cycle of the apparatus. A system for fume extraction will be

incorporated into the cover to avoid the build up of potentially harmful or

explosive gases.

Upon a main deck 108 (see Figure 2) are a locating stand 110 for the

mixing vessel 42, a large capacity test tube stand 112. and a stand 114

for a single test tube as well as the filter stand 102. The locating stand 110 is supported upon a mixing vessel balance 130. Upon a raised deck

116 (again labelled in Figure 2) there is in this particular embodiment a

well plate 118 containing a bank of individual vials for receiving doses of

fluid, and a waste well 120 into which rinsing fluid is discharged, the

waste well communicating with a fluid tank concealed within the chassis

104.

Fluid connections within the apparatus are schematically represented in

Figure 9. It can be seen that the ultrasonic flow cell 84 is connected to the

siphon tube 80 to draw liquid from the mixing vessel 42 when required

under the action of a pump 122 coniiectable (via a first valve 124, which

in this embodiment is of three port type) to the flow cell's outlet. The

pump is of displacement type and is capable of providing a metered fluid

dose under CPU control. Its side remote from the first valve is led to the

filter 100 and is thence coniiectable (via a second valve 126, again of

three port type in this embodiment) to the dispensing tubes 66 carried by

the liquid handling arm 52. A clean solvent tank 128 is connected to both

the first and second valves 124, 126, to supply solvent for flushing

purposes. The use of the apparatus to prepare a batch of solutions containing the

active pharmaceutical components of a corresponding batch of tablets

will now be described.

The batch of tablets is first loaded into the bowl feeder 12 by an operator

who then activates the apparatus. After this the process can be wholly

automatic, under CPU control. Each solution is prepared using a sample

consisting of a chosen number of tablets, which may be one or may be

two or more. The chosen number of tablets is delivered to the hopper 20

by means of the bowl feeder. At this stage the hopper 20 is carried upon

its stand 32 as seen in Figure 5. The balance 48 is used to weight the

tablets in the hopper to a high degree of accuracy (the illustrated

embodiment has a balance which is accurate to five decimal places, when

reading in grams) and the weight is recorded by the CPU. The hopper 20

is then lifted by means of the mechanical handling arm 50, whose jaws 62

engage with the upper cylindrical portion 28 of the hopper, which thus

stays closed against escape of the tablets until the hopper is placed upon

the neck of the mixing vessel 42 and its upper part 22 depressed to release

the tablets into the vessel. The hopper 20 is then replaced upon its stand

32 and released by the jaws 62. The mechanical handling ami is then used

to lift a test tube from the test tube stand 112 and place it in the

cylindrical portion 28 of the hopper. The test tube is thus ready to be weighed. The mechanical handling arm is then withdrawn from the

vicinity of the hopper.

The liquid handling arm 52 is used to dispense a desired quantity of

solvent into the mixing vessel 42. For the sake of accuracy, the solvent

quantity is to be measured by weight. The process can in some prior art

devices be time consuming, involving successive weighing and dosing

stages. However a relatively rapid method is adopted in the present

embodiment. After zeroing of the mixing vessel balance 130 with the

mixing vessel 42 in place, the displacement pump 122 is used to supply a

chosen proportion of the total required solvent. In the present

embodiment the proportion is 95%. This quantity is of course subject to a

degree of error, so the next step is to weigh the vessel 42 and its content

to obtain the mass of solvent delivered. The quantity of solvent required

to achieve 100% of the required dose is then calculated and delivered.

Again the displacement pump 122 serves to meter the solvent quantity

supplied. The final weight of solvent is verified using the mixing vessel

balance 130. The liquid handling arm 52 is withdrawn to a safe position.

The mixing vessel 42, now containing a chosen number of tablets and a

known quantity of solvent, is grasped using the jaws 62 of the mechanical

handling arm 50 and moved to the mechanical homogeniser 67, its neck , being engaged with the homogeniser's seal 73 to prevent escape of the

mixture. The homogeniser is run for a chosen period to break the tablets

down to fine particles. Some heating is caused by this process, but

because total dissolution of the active ingredients need not be achieved by

means of the mechanical homogeniser, the duration of this step - and the

consequent heating - can be limited. The homogeniser continues to run to

maintain a uniform suspension of tablet particles in the solvent while a

chosen quantity of the suspension is withdrawn through the siphon tube

80, the quantity being metered by means of the displacement pump 122.

The liquid thus withdrawn is passed first through the ultrasonic flow cell

84, where sonication promotes dissolution of the active pharmaceutical

components, and then through the filter 100, to remove the particulate

carrier material. Alternatively, all of the suspension may be progressively

withdrawn through the siphon tube 80 (the homogeniser again being run

to maintain a uniform suspension of tablet particles in the solvent) and

passed through the ultrasonic flow cell 84, where sonication again

promotes dissolution of the active pharmaceutical components. As the

liquor containing the active material in solution and the insoluble

components of the tablet in suspension exits the ultrasonic flow cell, it is

returned to the mixing vessel 42. This cycle will continue for a specific

time to a point where total dissolution of the active material has been

achieved and the concentration of active material is uniform throughout the liquor. The resultant liquor is then passed through the filter 100, to

remove the particulate carrier material.

A metered dose of the resulting homogeneous solution is then supplied to

the test tube carried by the hopper 20, and its weight is verified using the

balance 48. Typically this dose is to be diluted, and this can be achieved

in a two stage process similar to the one described above. Using the liquid

handling arm 52, a metered dose of solvent (e.g. 95% of the required total

dose) is discharged into the test tube, which is then weighed so that the

additional fluid needed to achieve the full dose can then be calculated by

the CPU and discharged into the tube. Again the final weight can be

checked to verify that the correct amount of solvent has been supplied.

The solution is then mixed. In the present embodiment this is achieved by

bubbling gas (more specifically air, although other gases could in

principle be used) through the solution using the liquid handling arm 52.

If further dilution is necessary, this can be achieved by moving the tube

containing the dilute solution to the single test tube stand 114 using the

mechanical handling arm 50, then collecting a further test tube using the

arm and placing it upon the hopper 20 for weighing. Using the liquid

handling arm 52, and in a two stage fill processes of the type just

described, measured doses of (a) the dilute solution and (b) the solvent

are discharged into the further test tube, whose contents are then mixed by bubbling of air through them. The dilution cycle can be repeated as

many times as necessary.

The final solution obtained using the apparatus may be left in its test tube,

which is returned to the large capacity stand 112 using the mechanical

handling arm 50 at the end of the process. Alternatively, as in the

illustrated embodiment, the solutions may be sipped from the test tube

using the liquid handling arm 52 and discharged into the vials in the well

plate 118. If desired, several vials may receive solution from a single trial,

so that multiple separate tests can be carried out.

The process is of course to be repeated numerous times in order to

process the entire batch of tablets. It is necessary to ensure that all

relevant parts of the apparatus are washed before the process re¬

commences, to prevent active components from one sample of the tablets

from contaminating the next The cleaning process will now be described.

Cleaning of the mixing vessel 42 and the homogeniser 67 is simultaneous.

The mixing vessel is emptied of unwanted solution by using the

mechanical handling arm and jaws to present the mixing vessel 42 up to

the homogeniser. An airtight seal is achieved between the vessel neck

and the homogeniser by pushing the neck of the vessel against the elastomeric seal 73. The vessel 42 is then pressurised with gas (air) with

the result that the liquid in the vessel is expelled via the siphon tube 80

into a waste collection vessel. Internal vessel pressure is then vented to

atmosphere. Cleaning fluid is then pumped through the dispensing tubes

78 and, emerging as high velocity jets through the apertures 77 in the

walls of these tubes 78, the internal surfaces of the mixing vessel and the

outside surfaces of the homogeniser are rinsed.

Once a sufficient quantity of cleaning fluid has accumulated in the

mixing vessel, the homogeniser is switched on at high speed for set times

with intermittent short settling pauses to cause maximum agitation and

turbulence in the fluid and to encourage Hie fluid to splatter over all

internal surfaces of the vessel and external surfaces of the homogeniser.

The homogeniser is designed in such a way that whilst running, fluid is

drawn into me open end of the homogeniser tube 70 and expelled through

the radial facing apertures 77 in the tube after passing over the

homogeniser blades. This current of cleaning fluid will clean the internal

features of the homogeniser.

After a set time the homogeniser is switched off and the whole cleaning

cycle repeated, starting with pressurisation of the vessel. This vessel/homogeniser cleaning program might be repeated as

necessary. Used test tubes are placed back in the large test tube rack

unwashed.

Cleaning of the fluid circuit depicted in Figure 9 is effected by flushing

with solvent in a two stage process. Bold arrows in the drawing show the

fluid's path during the first stage,, in which the first valve is used to

connect the filter's output side (i.e. its side which is downstream in

normal use) to the tank of clean solvent 128. Solvent is drawn by the

pump 122 through the filter 100, pump 122 and ultrasonic flow cell 84 to

wash all these parts and their connecting conduits. The cleaning fluid

passes through the filter in its reverse direction - that is, in the direction

opposite to the normal "in use" flow direction., serving to clear the filter

and its associated conduits and valves of both insoluble particles and

active material in solution. Subsequently cleaning fluid is passed in a

forward direction to remove traces of the active material in solution from

the filter and its associated conduits and valves.

Material retained upon the filter - including the particulate filler material

- tends to be driven off the filter, which is thereby washed for re-use.

This backwashing of the filter is not expected to remove all the retained material, but build up on the filter is slight and typically the filter will not

require replacement during the processing of an entire batch of tablets. It

is of course desirable - and in many instances necessary - to ensure that

active pharmaceutical ingredients do not build up on the filter, to avoid

contamination of one sample by the next, but thorough dissolution and

the washing process ensure this. After completion of the first flushing

step, the first and second valves are switched to carry out the second step.

Solvent flows in the direction indicated by faint arrows in Figure 9, to

wash remaining parts of the circuit.

Note that for certain applications the filter could be disposed of and

replaced for each trial, instead of being backwashed and re-used.

Multiple wash cycles can be carried out if need be, to ensure the required

level of cleanliness, although throughput will be correspondingly reduced.

Claims

An apparatus for processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

apparatus comprising

an arrangement for preparing a mixture containing one of the samples and

a predetermined quantity of solvent;

a mechanical homogeniser which is arranged to act upon the mixture and

to break down the solid preparation to form a particulate suspension

thereof in the solvent;

an ultrasonic actuator which is arranged to ultrasonically excite the

suspension and so to promote dissolution of the active material; and

an output arrangement for outputting the resulting solution to a sample

vessel.

2. An apparatus as claimed in claim 1 in which the ultrasonic actuator

forms part of a flow cell, being coupled to a fluid conduit through which

the suspension is passed.

3. An apparatus as claimed in claim 2 in which the flow cell is provided

with a cooling arrangement.

4. An apparatus as claimed in claim 3 in which the cooling arrangement

comprises a coolant path through the flow cell.

5. An apparatus as claimed in claim 4 which further comprises a Peltier

type cooler for providing coolant to the flow cell.

6. An apparatus as claimed in any preceding claim in which the ultrasonic

actuator is a piezoelectric device.

7. An apparatus as claimed in any preceding claim in which the

mechanical homogeniser is a rotary device.

8. An apparatus as claimed in claim 7 in which the mechanical

homogeniser is driven by an electric induction motor.

9. An apparatus as claimed in claim 8 in which the homogeniser is

provided with a siphon tube for withdrawing the suspension.

10 An apparatus as claimed in claim 9 in which the homogeniser is

provided with dispensing tubes for cleaning a vessel positioned around

the homogeniser.

11. An apparatus as claimed in any preceding claim further comprising a

filter arranged to receive the solution after its excitation by the ultrasonic

actuator and to remove particulate material from it

12. An apparatus as claimed in claim 11 further comprising an

arrangement of conduits and valves for passing cleaning fluid through the

filter, in a direction opposite to the direction of passage of the solution, to

back wash the filter between uses.

13. An apparatus as claimed in any preceding claim further comprising an

automatic sample supply device for supplying the solid samples

sequentially.

14. An apparatus as claimed in claim 13 in which the sample supply

device is a bowl feeder.

15. An apparatus as claimed in any preceding claim further comprising at

least one electronic balance.

16. An apparatus as claimed in any preceding claim further comprising at

least one robotic handling device.

17. An apparatus as claimed in claim 16 comprising a mixing vessel for

receiving the sample and the predetermined quantity of solvent, the

mixing vessel and the mechanical homogeniser being provided with

complementary sealing features so that the mixing vessel is able to be

presented to the mechanical homogeniser by means of the handling

device and to form a seal with it which prevents escape of the mixture

during homogenisation.

18. An apparatus as claimed in claim 16 or claim 17 further comprising a

hopper for receiving and conveying the solid samples.

19. An apparatus as claimed in claim 18 in which the hopper comprises at

least first and second interengaging parts shaped such that the hopper is

able to be suspended through the first part, causing the hopper to adopt a

configuration in which the second part is supported by the first and the two parts together define a downwardly closed receptacle for receiving

the sample, but by placing the receptacle upon a supporting surface the

second part is raised relative to the first, opening the receptacle

downwardly so that the sample is released from it

20. An apparatus as claimed in claim 18 or claim 19 in which the hopper

is additionally shaped to serve as a test tube stand.

21. An apparatus as claimed in any of claims 18 to 20 further comprising

a stand for the hopper which is mounted upon a balance, allowing the

hopper to be used in the manner of a balance pan to weigh its contents.

22. An apparatus as claimed in any of claims 16 to 21 comprising a

robotic liquid handling device arranged to output each solution produced

by the apparatus to a separate container.

23. An apparatus for processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

apparatus comprising an arrangement for preparing a mixture containing one of the samples and

a predeteπnined quantity of solvent;

a dissolution device for dissolving active components of the solid

preparation in the solvent;

a filter and associated conduits and a pump for passing at least some of

the resulting fluid through the filter in a forward direction to remove

particulate material from it; and

an output arrangement for outputting the resulting solution to a sample

vessel;

the device being characterised in that it further comprises valves and

conduits for passing cleaning fluid through the filter in a reverse direction,

opposite to the forward direction, to back wash the filter between

processing of the samples.

24. An apparatus as claimed in claim 23 in which valves are connected to

the inlet and to the outlet of the filter, to selectively connect it (a) between

the dissolution device and the output arrangement and (b) between a

source of cleaning fluid and a drain.

25. A method of processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

method comprising

preparing a mixture containing one of the samples and a predetermined

quantity of solvent;

mechanically homogenising the mixture to break down the solid

preparation to form a particulate suspension thereof in the solvent;

ultrasonically exciting the suspension and promoting dissolution of the

active material; and

outputting the resulting solution to a sample vessel,

these steps being repeated for each sample.

26. A method as claimed in claim 25 further comprising applying cooling

during either or both of the mechanical homogenisation and ultrasonic

excitation steps.

27. A method as claimed in claim 25 or claim 26 further comprising

passing the solution produced by the ultrasonic excitation step through a

filter in a forward direction before it is output, the method further

comprising back washing the filter by passing cleaning fluid through it in

a reverse direction prior to processing of the next sample.

28. A method as claimed in any of claims 25 to 27, further comprising

weighing the sample before it is processed.

29. A method as claimed in any of claims 25 to 28 further comprising

dispensing a required quantity of fluid by:

dispensing a first metered dose of fluid, which is smaller than the

required quantity but is a large proportion of it;

weighing the first dose of fluid;

calculating, based upon the weight of the first dose, the additional

quantity of fluid required to achieve the required quantity; dispensing the calculated additional quantity of fluid in a second metered

dose.

30. A method as claimed in claim 29 in which the dispensed fluid is

solvent used in the said mixture.

31. A method as claimed in claim 29 in which the dispensed fluid is the

processed solution.

32. A method as claimed in any of claims 29 to 31 in which the first

metered dose is more than 70% of the required quantity.

33. A method as claimed in claim 32 in which the first metered dose is

substantially 95% of the required quantity.

34. A method as claimed in any of claims 25 to 33 in which mechanical

homogenisation is carried out in a mixing vessel, which is subsequently

washed by adding cleaning fluid to the vessel and rumiing a mechanical

homogeniser in it.

35. A method as claimed in claim 34 in which the mixing to vessel is

emptied by gas pressurising it to force liquid out.

36. A method as claimed in any of claims 25 to 35 in which the ultrasonic

excitation is carried out using a flow cell, having an input and an output,

through which the suspension is passed.

37. A method as claimed in claim 36 in which, for a finite period, the

suspension output is re-circulated from the flow cell's output to its input,

to achieve a desired level of dissolution.

38. A method of processing multiple samples of a solid preparation to

provide a set of solutions each of which corresponds to one of the

samples and contains dissolved active material extracted from it, the

method comprisin igg

preparing a mixture containing one of the samples and a predetermined

quantity of solvent;

dissolving active ingredients of the sample in the solvent;

passing the solution produced by the ultrasonic excitation step through a

filter in a forward direction; outputtiug the resulting solution to a sample vessel; and

back washing the filter by passing cleaning fluid through it in a reverse

direction;

these steps being repeated for each sample.

39. An apparatus substantially as herein described with reference to, and

as illustrated in, the accompanying drawings.

40. A method substantially as herein described with reference to, and as

illustrated in, the accompanying drawings.