U.S. patent application number 11/160552 was filed with the patent office on 2006-02-02 for investigating different physical and/or chemical forms of materials.
Invention is credited to Daniel Cowell, Ryszard Jurek Kobylecki, Vassilis Stylianopoulos.
Application Number | 20060025934 11/160552 |
Document ID | / |
Family ID | 9889412 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060025934 |
Kind Code |
A1 |
Kobylecki; Ryszard Jurek ;
et al. |
February 2, 2006 |
INVESTIGATING DIFFERENT PHYSICAL AND/OR CHEMICAL FORMS OF
MATERIALS
Abstract
Apparatus and a method are described for investigating
polymorphs of a material, isomers of a material which allow
different isomeric forms to be resolved, different
hydrates/solvates and/or different salts of a material. The
apparatus comprises an assembly (2) of reactor devices (6) arranged
within a reactor body (8) which incorporates a heating/cooling
block (10) and a stirrer block (12). A vessel support block (14)
supports respective sample vessels (15) below each reactor device
(6) for receiving material from the reactor devices. The apparatus
includes a control unit (4) which includes a computer (16) which
controls a robot for delivering materials to the reactor devices; a
heating/cooling unit (18); a stirrer control unit (20); and a
pressure unit (22) which controls the passage of material from the
reactor devices (6) to the sample vessels (15).
Inventors: |
Kobylecki; Ryszard Jurek;
(Cambridgeshire, GB) ; Cowell; Daniel; (Cambridge,
GB) ; Stylianopoulos; Vassilis; (Cambridge,
GB) |
Correspondence
Address: |
MARTIN & HENSON, P.C.
9250 W 5TH AVENUE
SUITE 200
LAKEWOOD
CO
80226
US
|
Family ID: |
9889412 |
Appl. No.: |
11/160552 |
Filed: |
June 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10018034 |
Jul 23, 2002 |
6965832 |
|
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PCT/GB01/01593 |
Apr 9, 2001 |
|
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11160552 |
Jun 28, 2005 |
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Current U.S.
Class: |
702/27 |
Current CPC
Class: |
Y10T 436/25375 20150115;
B01J 2219/00351 20130101; Y10T 436/115831 20150115; B01J 2219/00585
20130101; B01J 2219/00308 20130101; B01J 2219/00698 20130101; B01J
19/0046 20130101; B01J 2219/00479 20130101; B01J 2219/00416
20130101; B01J 2219/00495 20130101; B01J 2219/00283 20130101; B01J
2219/00418 20130101; B01L 3/5025 20130101; B01L 3/50255 20130101;
B01J 2219/00689 20130101; C40B 40/00 20130101; B01J 2219/00704
20130101; Y10T 436/25 20150115; Y10T 436/11 20150115; B01J
2219/0059 20130101; B01J 2219/00288 20130101 |
Class at
Publication: |
702/027 |
International
Class: |
G01N 31/00 20060101
G01N031/00; G06F 19/00 20060101 G06F019/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 4, 2000 |
GB |
0008563.9 |
Claims
1. A method of investigating the crystal habit of a selected
material, comprising: (A) providing a plurality of receptacles; (B)
depositing a selected quantity of a selected initial material into
each said receptacle, (C) subjecting said initial material to a
first series of selected treatments, having selected first
treatment variables, to form a resultant material in each of said
receptacles wherein said treatments are controlled by a computer;
and (D) analyzing said resultant material to determine the crystal
habit thereof and generating crystal habit data related
thereto.
2. A method according to claim 1 including associating said crystal
habit data of each said resultant material with said treatment
variables.
3. A method according to claim 2 including storing said associated
crystal habit data and said treatment in said computer.
4. A method according to claim 1 wherein said computer is
programmed to select said treatment.
5. A method according to claim 1 including subjecting said
resultant material to a second series of selected treatments.
6. A method according to claim 5 wherein said second series of
selected treatments is selected by said computer depending upon the
crystal habit data of said resultant material.
7. A method according to claim 1, wherein said first treatment
variables include solvent variables.
8. A method according to claim 7, wherein said solvent variables
are selected from one or more of the following: (A) a first solvent
variable relating to the number of solvents used for preparing said
resultant material from said initial material; (B) a second solvent
variable relating to the timing of the addition of the solvent or
solvents into said receptacle; (C) a third solvent variable
relating to the amount of a solvent or solvents used in a
treatment; and (D) a fourth solvent variable relating to the
identity of a solvent or solvents used.
9. A method according to claim 8, wherein at least two of said
solvent variables are varied in a single series of experiments
and/or in multiple series of experiments.
10. A method according to claim 8, wherein the implementation of
said solvent variables is under the control of said computer.
11. A method according to claim 1, wherein said first treatment
variables includes a duration variable wherein said initial
material is treated for a selected duration.
12. A method according to claim 1, wherein said first treatment
variables includes a heating variable wherein said initial material
is subjected to a heating means.
13. A method according to claim 12, wherein said heating variable
is selected from one or more of the following: (A) a first heating
variable relating to the time of operation of said heating means;
(B) a second heating variable relating to the duration of operation
of said heating means; and (C) a third heating variable relating to
whether operation of said heating means is continuous or in
stages.
14. A method according to claim 1, wherein said first treatment
variables includes a cooling variable wherein said initial material
is subjected to a cooling means.
15. A method according to claim 1, wherein said first treatment
variables includes an agitation variable wherein said initial
material is subjected to agitation.
16. A method according to claim 15, wherein said agitation variable
is selected from one or more of the following: (A) a first
agitation variable relating to the time of operation of an
agitation means for agitating material; (B) a second agitation
variable relating to the duration of operation of said agitation
means; (C) a third agitation variable relating to whether operation
of said agitation means is continuous or in stages; and (D) a
fourth agitation variable relating to the rate of operation of said
agitation means.
17. A method according to claim 1, wherein a temperature profile is
defined for each said receptacle and wherein temperature profile
data relating thereto is stored in said computer.
18. A method according to claim 1 wherein said receptacles include
a porous member that is porous to fluids but not to said initial
material.
19. A method according to claim 1 including the application of
pressure to said receptacles during said first series of selected
treatments.
20. A method according to claim 19 wherein application of said
pressure is controlled by said computer.
21. A method according to claim 1 wherein said first series of
selected treatments includes the addition of liquid to at least one
of said receptacles and wherein said liquid is removed from said
receptacles and analyzed.
22. A method according to claim 1 including analyzing said crystal
habit data to identify (A) polymorphs of said initial material; (B)
hydrates/solvates of said initial material; or (C) salts of said
initial material.
23. A method according to claim 1 wherein said initial material is
subjected to a range of potential salt forming materials and
wherein said resultant material formed thereby is a salt of said
initial material.
24. A method according to claim 24 wherein said resultant material
is in a crystalline form.
25. A method to determine the crystal habit of a selected material
thereby to investigate polymorphs, hydrates/solvates, or salts of
said selected material, comprising: (A) providing a plurality of
receptacles; (B) depositing a selected quantity of a selected
initial material into each said receptacle, (C) subjecting said
initial material to a first series of selected treatments, having
selected first treatment variables, to form a first resultant
material in each of said receptacles wherein said treatments are
controlled by a computer; and (D) analyzing said first resultant
material to determine the crystal habit thereof; and (E) generating
first crystal habit data from said analysis of said first resultant
material.
26. A method according to claim 25 including subjecting said first
resultant material to a second series of selected treatments,
having selected second treatment variables, to form a second
resultant material.
27. A method according to claim 26 wherein said second treatment
variables are selected by means of a computer.
28. A method according to claim 26 wherein said second treatment
variables are different from said first treatment variables.
29. An investigation apparatus for investigating the crystal habit
of an initial material wherein said initial material is subjected
to selected treatment conditions thereby to investigate polymorphs,
hydrates/solvates, or salts of said initial material, said
investigation apparatus comprising (A) a reactor assembly including
(1) a reactor body having an internal region; and (2) an array of
receptacles disposed in the internal region adapted for receiving a
selected quantify of the initial material to be investigated; and
(B) a control unit in communication with said reactor assembly and
including a computer operative to control said selected treatment
conditions.
30. An investigation apparatus according to claim 29 wherein said
reactor assembly includes a heating/cooling block operative to
subject a selected temperature to said initial material in said
receptacles.
31. An investigation apparatus according to claim 29 wherein said
reactor assembly includes a stirrer block operative to agitate said
initial material in said receptacles.
32. An investigation apparatus according to claim 29 wherein said
reactor assembly includes (A) a plurality of collection vessels
located in the interior region of said reactor assembly, each said
collection vessel being in fluid communication with one of said
receptacles; and (B) a collection vessel support block adapted to
support said plurality of collection vessels.
33. An investigation apparatus according to claim 29 wherein said
control unit operative to selectively vary the temperature during
treatment of said initial material.
34. An investigation apparatus according to claim 29 wherein said
control unit includes a stirrer control unit operative to
selectively agitate said initial material during treatment
thereof.
35. An investigation apparatus according to 29 wherein said control
unit includes a pressure unit operative to control a selected
pressure during treatment of said initial material.
36. An investigation apparatus according to claim 29 where said
receptacles are associated with means for condensing vapour for
reducing loss of material therefrom by evaporation.
37. An investigation apparatus according to claim 36 wherein said
receptacles include a porous member adapted to support said initial
material when deposited therein, said porous member being porous to
fluids but not to said initial material.
38. An investigation apparatus according to claim 37 including a
pressure means operative to apply pressure within the internal
region thereby to restrict the passage of fluids from said
receptacles under gravity.
39. An investigation apparatus according to claim 38 wherein said
pressure means is controlled by said computer.
40. An investigation apparatus according to claim 29 including (A)
a material supply means adapted to contain selected materials to be
deposited into said receptacles; and (B) a delivery means for
transporting said selected materials from said supply means to a
selected one of said receptacles.
41. An investigation apparatus according to claim 29 including an
input means for inputting analytical data relating to material
produced after treatment of said initial material into said
computer, wherein said computer is programmed to analyse data input
into it and determine variables to be used in a subsequent
investigation on the same initial material, using said
apparatus.
42. An investigation apparatus according to claim 29 for making a
library of products.
43. An investigation apparatus according to claim 29 for effecting
automatically a multiplicity of treatments of an initial material
which treatments differ in at least one experimental variable.
Description
FIELD OF THE INVENTION
[0001] This invention relates to investigating different physical
and/or chemical forms of materials and particularly, although not
exclusively, provides an apparatus for and a method of carrying out
such investigations. Preferred embodiments relate to the
investigation of polymorphs of materials; resolution of isomeric
mixtures; and investigating suitable salts of active materials
(e.g. pharmcologically active materials).
BACKGROUND
[0002] Different polymorphs, crystal habits, hydrates/solvates and
salts of chemical compounds, for example drugs, generally exhibit
marked differences in key properties, such as bio-availability,
solubility, density, shock sensitivity, product stability and
shelf-life and such properties affect the efficacy of the drugs. It
is, therefore, important to optimise the physical and chemical
properties of a drug candidate in order to select the best
candidate for use in clinical trials.
[0003] Other non-drugs and/or inorganic/organic materials, for
example pigments or dyes may also exhibit different properties in
dependence upon their form.
[0004] Polymorphism is the existence of a substance in two or more
forms which are significantly different in physical or chemical
properties. The existence of polymorphs of, for example, a drug
candidate, can cause problems particularly when scaling-up
processes, since a scaled-up process may produce a polymorph having
different properties from a polymorph prepared in lab-scale
experiments. Thus, pharmaceuticals companies ideally need
information on polymorphs of any drug candidates, including an
understanding of processing conditions which favour production of
particular polymorphs. By way of example, the Journal of
Pharmaceutical and Biomedical Analysis Vol. 3. No. 4. pp 303-313,
1985 describes the polymorphism of the drug cimetidine and
illustrates how process conditions may be adjusted to prepare
particular polymorphs.
[0005] In general, current investigations of polymorphs of drug
candidates are undertaken by trial and error which involves running
a series of, for example, re-crystallisations of a drug candidate
using a range of different re-crystallisation conditions and then
analysing the re-crystallised products.
[0006] Another approach to investigating polymorphs involves
computer modeling of drug candidates, for example by calculating
what crystal forms could theoretically be prepared and calculating
energy minima of such forms. Such an approach may help to focus
re-crystallisation experiments directed at preparing each form
theoretically identified.
[0007] One way of separating an isomeric, for example a
diastereomeric, mixture of a material is to prepare diastereomeric
salts of the material which have different crystallisation
properties thereby allowing the salts to be separated by
recrystallisation. Currently, the identification of relevant
separable diastereomeric salts is by trial and error and is
extremely time-consuming and tedious.
[0008] Many drugs are administered in salt form. Desirable
properties of such salts include having a melting point in the
range 150-200.degree. C., solubility in common solvents, stability,
minimum hygroscopicity etc. Furthermore, it is desirable to have
polymorphism information on any proposed salt form. However,
currently the preparation of suitable salt forms is carried out by
trial and error and, accordingly, is not optimized.
SUMMARY OF THE ASPECTS OF THE EXEMPLARY EMBODIMENT
[0009] It is an object of the present invention to address the
above described problems.
[0010] According to a first aspect of the invention, there is
provided a method of investigating different physical and/or
chemical forms of a material, the method comprising: [0011]
providing an array of receptacles each containing material
(hereinafter "said initial material") to be investigated; [0012]
subjecting said initial material in respective different
receptacles to respective different treatments under the control of
a computer; and [0013] analysing any material resulting from said
different treatments (hereinafter "said resultant material").
[0014] Preferably, the method includes associating data relating to
the analysis of each resultant material with information relating
to the treatment used to prepare said resultant material from said
initial material.
[0015] Preferably, data relating to said analysis is stored in said
computer and associated with said information relating to the
treatment as aforesaid. Preferably, said computer is programmed to
determine treatments to which initial material in receptacles is to
be subjected. Said computer may determine treatments in dependence
upon the results of the analysis of resultant material in a first
series of experiments using said array. Thus, treatments may be
determined by said computer for a second series of experiments
following said first series. The first series of experiments may be
determined manually by a user or may be determined by the computer,
for example, randomly (since no analysis may be available on which
to base a more focussed determination).
[0016] Said initial material is preferably a solid. The method
preferably involves inputting a predetermined amount of said
initial material into each receptacle. For example a weighed amount
may be input into each receptacle. This may be done manually by a
user or may be undertaken automatically, for example by a robot,
suitably under the control of said computer.
[0017] There is no limit on the amount of material that may be
input into the vessels. Amounts as small as 0.1 mg or as large as
0.5 Kg may be used. Advantageously, however, relatively small
amounts may be used.
[0018] Said different treatments to which initial material is
subjected to prepare resultant material may include variable(s)
relating to the solvent or solvents used in the treatments
(hereinafter referred to as "solvent variables"). A first solvent
variable may be the number of solvents used for preparing resultant
material from initial material. For example, in one receptacle of
the array only one solvent may be used in a treatment, whereas in
another receptacle two or more solvents may be used. A second
solvent variable may relate to the timing of the addition of the
solvent or solvents into a receptacle. For example, the total
amount of solvent to be used in a treatment in one receptacle of
the array may be input into the receptacle at the start of the
treatment, whereas in another receptacle, the solvent may be input
in stages or, if two solvents are used, one may be input at the
start of the treatment and another may be input later. A third
solvent variable may be the amount of a solvent or solvents used in
a treatment. The total amount of solvent used may vary between wide
limits and will, of course, depend upon the amount of initial
material used. Advantageously, the total amount of solvent in one
receptacle may be less than 10 ml, preferably less than 5 ml. A
fourth solvent variable may be the identity of a solvent or
solvents used. Solvents used may be selected from any solvent that
may be used for crystallisation of a material--examples include
acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate,
tert-butylmethyl ether, cumene, dimethylsulphoxide, ethanol,
ethylacetate, ethyl ether, ethyl formate, formic acid, heptane,
isobutyl acetate, isopropyl acetate, methyl acetate,
3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone,
2-methyl-1-propanol, pentanone, 1-pentanol, 1-propanol, 2-propanol,
propyl acetate and tetrahydrofuran.
[0019] Suitably, in the method, at least one, preferably at least
two, more preferably at least three, especially all of the
aforementioned solvent variables are varied in a single series of
experiments using said array and/or in multiple series of
experiments.
[0020] Whilst the solvent variables may be implemented manually,
their implementation is preferably under the control of said
computer and, accordingly, data relating thereto is preferably
stored in the computer. Preferably, said computer controls a robot
which introduces predetermined solvent(s) in respective
predetermined amounts into respective predetermined receptacles at
respective predetermined times.
[0021] Said different treatments to which initial material is
subjected to prepare resultant material may include a variable
relating to the duration of the treatment of said initial material
to prepare said resultant material (hereinafter "said duration
variable"). Said duration variable is preferably controlled by said
computer.
[0022] Said different treatments to which initial material is
subjected to prepare resultant material may include a variable
relating to the operation of a heating means during the treatments
(hereinafter referred to as "heating variables"). The method
preferably includes the step of the computer controlling a heating
means.
[0023] A first heating variable may relate to the time of operation
of said heating means. A second heating variable may relate to the
duration of operation of said heating means. A third heating
variable may relate to whether operation of said heating means is
continuous or in stages.
[0024] Whilst said heating means could be arranged to enable the
supply of heat to be individually varied for each respective
receptacle in said array, heat may be supplied to groups of
receptacles in the array in the same manner. Preferably, heat is
supplied to all members of the array in the same manner--that is
preferably there is no variation in the supply of heat across the
array.
[0025] Data relating to said heating variables is preferably stored
in said computer and preferably implementation of said variables is
controlled by said computer.
[0026] Said different treatments to which initial material is
subjected to prepare resultant material may include a variable
relating to the operation of a cooling means during the treatments
(hereinafter referred to as "cooling variables"). The method
preferably includes the step of the computer controlling a cooling
means.
[0027] Said cooling variables may include first, second and/or
third variables relating to time, duration and operation as
described above for said heating variables.
[0028] Said heating means and/or said cooling means may be used to
construct any possible heating/cooling profile for use in the
method.
[0029] Said different treatments to which initial material is
subjected to prepare resultant material may include variables
relating to the agitation of material in the receptacles during
treatment (hereinafter referred to as "agitation variables"). A
first agitation variable may relate to the time of operation of an
agitation means for agitating material. A second agitation variable
may relate to the duration of operation of said agitation means. A
third agitation variable may relate to whether operation of said
agitation means is continuous or in stages. A fourth agitation
variable may relate to the rate of operation of said agitation
means.
[0030] Whilst said agitation means could be arranged to
individually vary the agitation regime in each respective
receptacle, conveniently, groups of receptacles in the array are
subjected to the same agitation regime. For example, in an
8.times.12 array, each receptacle in a row of 8 receptacles may be
subjected to the same agitation regime, whereas the regime may be
varied between rows.
[0031] Data relating to said agitation variables is preferably
stored in said computer and, preferably, implementation of said
variables is controlled by said computer.
[0032] Preferably, a temperature profile is defined for each
receptacle in the array. Any temperature profile and any number of
different temperature profiles may be constructed for use in said
method. Data relating to the temperature profile is preferably
stored in the computer. It will be appreciated that the temperature
profile will be dependent upon a summation of all forms of energy
which impinge upon materials in the receptacles. For example, the
total energy supplied may be dependent upon the heating means,
cooling means and/or the agitation means.
[0033] The method may involve said initial material being supported
on a porous member which is porous to fluids but not to said
initial material, when in solid form. The method may include
applying a pressure to prevent solvent (s) passing out of the
receptacles, away from said initial material, during treatment of
the initial material. The application of said pressure may be
controlled by said computer. Said computer may, however, at a
predetermined time, reduce or remove the pressure and allow solvent
to pass through the porous member. The method may also include
applying a vacuum means to each receptacle to suck liquid away
therefrom, for example from solid material therein. Again,
suitably, operation of the vacuum means is under the control of the
computer.
[0034] In the method, said resultant material, which suitably
remains in said receptacles, may be analysed. Alternatively and/or
additionally, liquid removed from the receptacles may be analysed.
To this end, the method may include collecting liquid removed from
the receptacles in respective collection vessels. Analysis of said
resultant material and/or said liquid may be undertaken manually
that is, an operator may remove the material and/or liquid and
analyse it. Alternatively, however, analysis of said material
and/or said liquid may be undertaken automatically, suitably under
the control of said computer. For example material/liquid may be
automatically transferred, for example by a robot, to an analysis
apparatus, thereby to couple preparation and analysis of resultant
materials and provide a substantially fully automatic investigation
system.
[0035] Data from the analysis of said resultant material and/or
said liquid is preferably input into said computer, either manually
or automatically.
[0036] Analysis of said resultant material and/or said liquid may
be undertaken using one or more spectroscopic techniques, for
example IR techniques, NMR, diffraction techniques such as X-ray
diffraction, powder diffraction, single crystal diffraction, or by
one or more thermo analysis, for example differential scanning
calorimetry.
[0037] Said method may be for investigating polymorphs of a
material; for investigating isomers of a material which allow
different isomeric forms to be resolved; for investigating
different hydrates/solvates; and for investigating different salts
of a material.
[0038] Where the method is for investigating polymorphs of said
initial material, the initial material may be provided in the
receptacles and then subjected to different treatments wherein
treatments between receptacles in the array vary in terms of one or
more of said solvent variables described above; and/or duration
variables; and/or said heating variables; and/or said cooling
variables; and/or said agitation variables; and/or by having
different temperature profiles.
[0039] At the end of a treatment in a first series of experiments
using said array, said resultant materials (which will be, if
produced, re-crystallized forms of said initial material) are
suitably analysed to determine if different polymorphs have been
prepared. The computer may then determine the variables to be
adopted in a second series of experiments using said array, with a
view to locating any additional polymorph(s).
[0040] Where the method is for the resolution of isomers of said
initial material, then, firstly, the initial material may be
treated with a range of potential salt forming materials
(hereinafter "salt formers") with a view to preparing salts of said
initial material. For example, if said initial material is an acid,
said range of salt formers may be amines. After treatment with said
salt formers, the materials in said receptacles may be subjected to
the different treatments described above for investigating
polymorphs, suitably in order to re-crystallize predominantly one
isomer of a salt of the initial material. After such treatment,
either said resultant material may be analysed or liquid removed
from said receptacles may be analysed. As will be appreciated, if
the latter material shows the existence of a single diastereomer of
the salt, then the other diastereomer must be in the resultant
material.
[0041] Where the method is for investigating different salts of a
material, it may be used to select salts of the material that have
desirable properties of, for example solubility, toxicity, melting
point etc. In this case, in the method, the initial material is
treated with a range of potential salt forming materials ("salt
formers" as described above with reference to the resolution of
isomers). Thereafter, the material is subjected to the different
treatment described above for investigating polymorphs, suitably in
order to re-crystallize the salts of the initial material. At the
end of the treatments, each resultant material is analysed.
[0042] The invention extends to a method of examining the effect in
a treatment of a material of varying selected treatment variables,
the method comprising preparing a first resultant material from an
initial material using a first treatment using a first set of
experimental variables and preparing a second resultant material
from an initial material using a second treatment using a second
set of experimental variables, wherein said first and second
treatments are controlled by a computer. Preferably, a multiplicity
of different treatments are undertaken using an array of
receptacles.
[0043] The invention extends to a method of preparing a library of
resultant materials using an array of receptacles each of which
includes an initial material, the method comprising varying
selected treatment variables used to prepare resultant materials
from said initial material, wherein the treatments to which said
initial material are subjected are controlled by a computer.
[0044] The invention extends to a method of effecting automatically
the preparation of resultant materials from initial material, the
method comprising preparing resultant materials from initial
material using respective sets of physical and/or chemical
treatments, wherein data relating to said sets is stored by a
computer, and the treatments are undertaken under the control of
the computer.
[0045] According to a second aspect of the invention, there is
provided apparatus for investigating different physical and/or
chemical forms of a material, the apparatus comprising: [0046] an
array of receptacles for containing material (hereinafter "initial
material") to be investigated; [0047] treatment means for
subjecting initial material to respective different treatments; and
[0048] a computer arranged to control the respective different
treatments to which initial material is subjected.
[0049] A said receptacle may include a porous member which is
porous to fluids but not to said initial material. Said porous
member may define a wall, which may be a lower wall of the
receptacle, for supporting initial material. Said apparatus may
include pressure means for applying a pressure to restrict the
passage of fluid from the receptacle under gravity. Such pressure
means is preferably controlled by said computer.
[0050] Preferably, each receptacle in said array is as described
for said receptacle. Preferably, the receptacles in the array are
substantially identical to one another.
[0051] Said treatment means preferably includes temperature control
means for varying the temperature of materials contained in said
receptacles. Said temperature control means preferably includes a
heating means associated with said array of receptacles. For
example, said heating means may be a heater block, which may
include openings in which said receptacles are arranged. Said
heating means may be arranged for heating members of said array of
receptacles individually or in respective groups. Conveniently,
however, said heating means is arranged for heating each receptacle
in substantially the same manner.
[0052] Said temperature control means may include a cooling means.
Cooling of the receptacles may be effected by a reduction in the
amount of heat supplied by said heating means and/or by use of a
cooling means, for example a cooling coil (or the like), which is
at less than ambient temperature.
[0053] Operation of said heating means and/or said cooling means is
preferably controlled by said computer, suitably in a predetermined
manner.
[0054] Said temperature control means may be arranged to define any
shape of temperature profile for use in the treatment of said
initial material.
[0055] Preferably, means is associated with said receptacles for
reducing loss of material therefrom by evaporation. Suitably,
therefore, means is provided for condensing vapour in said
receptacles. A condenser means may be associated with each
receptacle, for example, by being fitted in an upper end
thereof.
[0056] Said treatment means preferably includes agitation means for
agitating, for example for stirring, material in said receptacles.
Said agitation means may be arranged for agitating the contents of
each receptacle in an individually controllable manner or groups of
receptacles may be arranged to be controlled in the same manner.
Preferably, said agitation means is arranged to be controlled by
said computer for stirring respective groups of receptacles in
substantially the same manner.
[0057] Said agitation means may include a stirrer block which may
include openings in which said receptacles are arranged.
[0058] Preferably, respective collection means are associated with
each receptacle in the array for collecting fluid passing out of
the receptacles. Said respective collection means are preferably
arranged directly underneath respective outlets of said receptacles
in the array.
[0059] Delivery means may be provided for delivering materials, for
example fluids, into the receptacles. Preferably, said delivery
means is controllable, suitably by said computer, for delivering
materials into respective receptacles. Said delivery means may be
arranged to select materials from a material supply means (which
suitably includes a multiplicity of different materials) and
deliver selected material (s) to a selected receptacle, suitably in
a predetermined amount and, suitably, at a predetermined time. Said
delivery means is preferably controlled by said computer. Said
delivery means is preferably a robot.
[0060] Said apparatus preferably includes input means for inputting
data relating to material (e.g. "resultant material" of the first
aspect) produced after treatment of said initial material, for
example, analytical data, into said computer. Preferably, said
computer is programmed to analyse data input into it and determine
variables to be used in a subsequent investigation on the same
initial material, using said apparatus. For example, said computer
may be programmed to determine variables which direct subsequent
investigations to parameter space which is different to parameter
space already investigated and/or parameter space which is
predicted (e.g. by software) to yield material with desirable
properties.
[0061] In one embodiment, analysis of material produced may be
undertaken manually and data relating thereto may be manually input
into the computer. In another embodiment, material produced may be
analysed automatically and data relating thereto may be
automatically input into the computer. For example, a robot may
remove material produced and arrange it for analysis by suitable
analytical apparatus; or material produced may be analysed without
removal from the apparatus. Analysis without removal may utilise
reflectance IR, reflectance UV, laser Raman scattering or XRD.
[0062] The invention extends to the use of apparatus according to
the second aspect for investigating different physical and/or
chemical forms of a material.
[0063] The invention extends to the use of apparatus according to
the second aspect in making a library of products.
[0064] The invention extends to a library of products in
combination with a database incorporating data for each product,
wherein said data relates to experimental variables for preparing
each product.
[0065] The invention extends to the use of apparatus according to
the second aspect in effecting automatically a multiplicity of
treatments of an initial material which treatments differ in at
least one experimental variable.
[0066] Any feature of any aspect of any invention or embodiment
described herein may be combined with any feature of any aspect of
any other invention or embodiment described herein.
[0067] Specific embodiments of the invention will now be described,
by way of example, with reference to the accompanying diagrammatic
drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0068] FIG. 1 is a schematic side view of investigation
apparatus;
[0069] FIG. 2 is a top plan view of a reactor assembly in the
direction of arrow II in FIG. 1, with individual reaction devices
omitted in the interests of clarity;
[0070] FIG. 3 is a detailed cross-section through a reaction device
arranged within the reactor assembly;
[0071] FIG. 4 is a detailed cross-section through an alternative
reaction device arranged within a reactor assembly; and
[0072] FIG. 5 is a schematic representation of an experimental
profile; and
[0073] FIGS. 6 to 10 summarise the solvents used in Experiments
which investigate polymorphs of cimetidine.
DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS
[0074] In the figures, the same or similar parts are annotated with
the same reference numerals.
[0075] The investigation apparatus shown in FIG. 1 comprises a
reactor assembly 2 and a control unit 4. The assembly 2 comprises a
12.times.8 array of reactor devices 6 (only one of which is shown
in FIG. 1) arranged within a reactor body 8 which incorporates a
heating/cooling block 10 and a stirrer block 12 which are
controllable for heating/cooling and stirring the contents of the
reactor devices 6. A vessel support block 14 supports respective
sample vessels 15 below each reactor device 6 for receiving
material from the reactor devices.
[0076] The control unit 4 includes a computer 16 which is arranged
to control: a robot (not shown) which delivers materials to the
reactor devices; a heating/cooling unit 18 which controls the
temperature of the reactor devices; a stirrer control unit 20 which
controls stirring of materials in the reactor devices; and a
pressure unit 22 which controls the passage of material from the
reactor devices 6 to the sample vessels 15.
[0077] In use, a range of different materials (e.g. bases, solvents
etc) may be added to the reactor devices (e.g. in predetermined
amounts and at predetermined times) by the robot; the materials may
be subjected to predetermined processes (e.g. heating/cooling and
stirring regimes) for predetermined times; and, thereafter,
material from each reactor device and/or sample vessel 15 may be
isolated and analysed, with relevant data relating to each of the
aforementioned being stored in the computer.
[0078] The investigation apparatus and its uses will now be
described in greater detail.
[0079] The reactor devices 6 are identical. Referring to FIG. 3,
the reactor device shown comprises an elongate cylindrical glass
vessel 24 having glass frits 26 providing a porous platform at its
lower end. (It will be appreciated that any type of filter device
may be used). Downstream of the frits the vessel includes an outlet
tube 28 having a female luer adaptor.
[0080] The stirrer block 12 surrounds a lower end of the reactor
device. The block incorporates a magnetic flux stirrer which is
arranged to cause movement of a stirrer bar (not shown) which is
arranged within cylindrical vessel 24. The stirrer block is
arranged such that it is controllable for stirring rows of eight
reactor devices in the array at the same rate but allowing
variation in the stirring between rows.
[0081] It is appreciated that the act of stirring the contents of
the reactor devices is a means of inputting energy. Accordingly,
not only are details of stirring rates of respective devices stored
in the computer but, additionally, data relating to the energy
input by such stirring is also stored.
[0082] An insulating plate 30 is provided above the stirrer block
12 for insulating it from the heating/cooling block 10 within which
the main part of the reactor device is arranged.
[0083] Block 10 comprises a heater which is finely controllable by
the computer 16. Cooling can be achieved simply by switching the
heater off. Whilst means could be provided for varying the
heating/cooling of individual reactor devices within the array, it
is found to be adequate to apply the same heating/cooling regime to
all reactor devices in the array at any one time.
[0084] A reflux condenser 32, having a water inlet 34 and outlet 36
is arranged within the reactor device 6 at its upper end. The use
of the condenser prevents loss of material by evaporation from the
reactor device and can aid cooling of the contents thereof.
[0085] As an alternative to the reflux condenser, or in addition
thereto, the reactor may include a cooling block. Referring to FIG.
4, the heating/cooling block 10 of FIG. 3 may be replaced with a
heating block 36 adjacent insulating plate 30, and a cooling block
38 which is spaced from the heating block 36 by insulating pillars
40. In the FIG. 4 embodiment, the computer is arranged to control
operation of both the heating and cooling blocks 36, 38.
[0086] As shown in FIG. 1, the reactor devices 6 are arranged
within reactor body 8, the internal region 42 of which is a sealed
unit when all ninety-six of the reactor devices 6 are in position
within the openings defined in the heating/cooling blocks 10 (or
36, 38) and stirrer blocks 12. Nitrogen gas is arranged to be
supplied, via line 44, into the internal region 42 for pressurizing
it and, in particular, for applying a pressure to prevent flow of
fluid, under gravity, through the frits of the reactor devices 6.
However, the nitrogen pressure can be removed when desired to allow
passage of fluids through the frits into the sample vessels 16, for
example at the end of an experimental procedure. Furthermore, a
vacuum line 46 communicates with the internal region 42 for
controlling the pressure with the region; for example a negative
pressure may be applied, to suck fluid through the frits 26 and/or
to help to dry solid material supported on the frits. A feedback
line 48 also communicates with the internal region for measuring
the pressure therewithin and relaying information to the control
unit 22. Operation of the control unit 22 which controls supply of
nitrogen and the application of a vacuum to the internal region is
under the control of the computer 16.
[0087] The computer 16 also controls the processes undertaken in
each of the reactor devices of the array. In this regard, a unique
identifier is assigned to each reactor device and a unique set of
process steps may be defined for each. The variables that may be
defined for each reactor device when investigating polymorphs
include: [0088] A(i) Solvent variables--these may be varied in any
respect and may include the identity of a solvent or solvents to be
added to a reactor device; the amount of the solvent or solvents to
be added; and the timing of the addition of the solvent or
solvents. For example, a mixture of solvents may be added at the
start of an experiment or one solvent may be added at the start and
another may be added five minutes after the start; or a first
amount of a solvent may be added at the start and a second amount
of the same solvent may be added later. In essence, through robotic
control the profile of the added solvent can be infinitely varied.
[0089] A(ii) Heating/cooling profile--operation of the
heating/cooling block 10 (or the separate heating and cooling
blocks 36, 38), for example the time of operation of the heating
block, the duration of heating, whether heating is in stages and
the cooling regime implemented are controlled by the computer,
thereby to define a temperature profile for each reactor device.
[0090] A(iii) Stirring rates--operation of the stirrer block, for
example the time and duration of its operation are controlled by
the computer. [0091] A(iv) Total time--the total time for any
particular experiment can be varied.
[0092] The apparatus may be used as follows in assessing polymorphs
of a particular compound.
[0093] The variables described under points A(i) and (iv) for each
reactor device are programmed into the computer to define
experimental profiles to which materials in the reactor devices are
subjected. An experimental profile for a reactor device is
illustrated in FIG. 5. The computer itself may be programmed to
illustrate profiles as shown in FIG. 5 for reference by an
operator. Referring to FIG. 5, the total time from start to finish
of the procedure is 3 minutes 30 seconds; the robot delivers
solvent 1 (S1) at the start of the procedure and later delivers
solvent 2 (S2) (details on the amounts of S1 and S2 are not shown
in FIG. 5); the temperature after addition of S1 is 20.degree. C.
and this is raised to 50.degree. C. and 60.degree. C. over a period
and then allowed to fall to 40.degree. C.; the stir rate is held
constant throughout and a positive nitrogen pressure is maintained
(thereby to maintain the fluid in the reactor device) until the end
of the experiment.
[0094] After the computer has been programmed, a measured amount of
the compound to be assessed is introduced into the reactor devices
so that it sits on the frits 26. A robot may deliver the compound
or, alternatively, it may be delivered manually. A multi-pipetting
x,y,z gantry type robot is, however, under the control of the
computer to deliver predetermined amounts of solvents from a
solvent area (for example comprising an 8.times.4 (or other sized)
array of different solvents arranged adjacent the investigation
apparatus) to the reactor devices. The predetermined experimental
procedures (aimed at causing the crystallisation of polymorphs of
the compound under investigation) are then carried out under
control of the computer.
[0095] At the end of the experimental procedures, the positive
pressure provided by the nitrogen supply is removed and a vacuum
applied to suck fluid out of the reactor devices. A wash cycle may
be carried out to wash any crystals present in the reactor devices.
After washing, the crystals may be removed, and analysed and
identified, for example by HPLC, laser Raman IR, conventional IR,
NMR, X-ray diffraction, powder diffraction, single crystal
diffraction and/or Differential Scanning Calorimetry. Analytical
data may then be input into the computer and associated with data
relating to the experiment procedures implemented in relation to
appropriate reactor devices. Also, if no crystals are retrieved,
then this fact is also input into the computer.
[0096] The computer is programmed to analyse the analytical
information in conjunction with the variables used in the
experimental procedures to determine the next set of experimental
procedures to be undertaken using the apparatus. Software sold
under the Trade Mark DIVA by Oxford Molecular Group pic of Oxford,
England may be used to undertake this task. For example, the
software may select subsequent experiments to explore previously
unexplored property space far away from property space previously
explored, to determine whether polymorphs exist in the unexplored
property space.
[0097] Thus, use of the apparatus described may maximize the
chances of all relevant polymorphs of a compound being is prepared
within the property space being examined in the defined procedure.
Furthermore, when a range of polymorphs have been prepared, the
most appropriate may be selected for further investigation, for
example clinical trials. Additionally, armed with knowledge of the
conditions which favour production of the identified polymorphs of
the compound, process conditions for plant preparation of the
desired polymorph may be controlled to minimize the risk of other,
undesired, polymorphs being inadvertently prepared.
[0098] The following example describes a procedure used to
investigate polymorphs of the known drug cimetidine; the procedure
can be applied to an investigation of any material.
[0099] Cimetidine was chosen since it is known to have several
polymorphs, and the literature teaches the difficulty experienced
in determining different physical forms of the material. The
following steps were undertaken:
[0100] 200 mg of commercially available cimetidine (Aldrich 28,
541-2) was loaded to each vessel 24 dry.
[0101] A set of 24 commonly used "pharmaceutically acceptable"
solvents (see list below) was chosen. The widely differing range of
physical properties e.g. boiling point, dielectric constant,
salvation propensity thus ensures a comprehensive coverage of
solvent property space.
[0102] Solvents
[0103] 1. MeOH
[0104] 2. EtOH
[0105] 3. IPA
[0106] 4. EtOAc
[0107] 5. IPE
[0108] 6. TBME
[0109] 7. DCM
[0110] 8. Toluene
[0111] 9. Iso-octane
[0112] 10. MEK
[0113] 11. Hexane
[0114] 12. Petroleum ether 80-100
[0115] 13. NMP
[0116] 14. MIBK
[0117] 15. DMF
[0118] 16. MeCN
[0119] 17. Acetone
[0120] 18. .sup.iPrOAc
[0121] 19. Dioxan
[0122] 20. THF
[0123] 21. Petroleum ether 60-80
[0124] 22. Water
[0125] 23. 2-methyl-1-propanol
[0126] 24. Diethyl ether
[0127] Thermal and stirring parameters were varied within a chosen
set of 96 sample vessels 24 according to a predetermined programme
or protocol in five separate experiments described below.
[0128] Experimental conditions--each of the set of five experiments
had a parameter space profile of a type as illustrated in FIG. 5.
The exact conditions used are appended to each experiment
[0129] Experiment 1
[0130] FIG. 6 summarises the solvents used in each of the 96
vessels in the array. The conditions used were as follows: Solid
charged; solvent(s) added and stirring started; held at 20.degree.
C. for 15 minutes; warmed to ca 85.degree. C./reflux and held for
15-20 mins; cooled to ca 30.degree. C. over 2 hours; filtered and
vacuum applied for ca 3 hours; products harvested and "evaporated
filtrate" samples also collected; samples run by IR to look for
polymorphic forms.
[0131] Experiment 2
[0132] FIG. 7 summarises the solvents used. The conditions used
were as follows: Solids charged and then solvents added; stirring
started; held at ca 20.degree. C. for 10 minutes; heated to ca
85.degree. C. and held for 10 minutes; cooled to ca 25.degree. C.
over 2 hours; filtered under vacuum and vacuum left on for ca 4
hours. Solids collected as well as "evaporative filtrate" samples;
analysed by IR for polymorphic forms.
[0133] Experiment 3
[0134] FIG. 8 summarises the solvents used. The conditions used
were as follows: Solids charged, solvents added and stirring
started; heated to ca 80.degree. C. and held for 70 minutes; cooled
to ca 25.degree. C. over 21/2 hours; filtered and vacuum left on
for ca 4 hours; solids/evaporated samples collected; analysed by IR
for polymorphic forms.
[0135] Experiment 4
[0136] FIG. 9 summarises the solvents used. The conditions used
were as follows: Solids and solvents charged and stirring started;
held at 20.degree. C. for 10 minutes; heated to ca
80.degree.-85.degree. C. and held for 15 minutes; cooled to ca
60.degree. C. over 30 minutes; held at ca 60.degree. C. for 1 hour;
cooled to 40.degree. C. over 30 minutes; held at ca 40.degree. C.
for 1 hour; cooled to 25.degree. C. over 1 hour; products harvested
by filtration under vacuum; solids collected by filtration and
evaporated samples analysed by IR for polymorphic forms.
[0137] Experiment 5
[0138] FIG. 10 summarises the solvents used. The conditions used
were as follows: Solids charged, solvent added and stirring
started; held at 20.degree. C. for 10 minutes; heated to
80.degree.-85.degree. C. and held for 5 minutes; cooled to ca
10.degree.-15.degree. C. over 30 minutes; cooled to
0.degree.-5.degree. C. and held for ca 11/2 hours; filtered under
vacuum and left under vacuum for ca 4 hours; samples collected from
vessels and dried in vacuum at 20.degree. C. for 2 hours (many
samples damp); evaporative samples also collected; analysed by IR
for polymorphic forms.
[0139] Results
[0140] Examination of the IR spectra revealed that different
polymorphs were produced in different sample vessels at alternate
areas of the polymorph space utilised. Polymorphs described
hereinafter are referred to as described in "The Polymorphism of
Cimetidine" J. Pharmaceutical and Biomedical Anal 3, No 4 P 303-313
(1985). In particular, polymorph A was detected in Experiment 1
vessel 3 (isopropyl alcohol); Experiment 1, vessel 4 (ethyl
acetate); Experiment 1, vessel 5 (diisopropyl ether), amongst
others. This polymorph was observed more frequently within the
parameter space examined, which is consistent with form A being the
form generally used.
[0141] Polymorph B was, for example, detected in Experiment 1
vessel 22 (water); Experiment 1, vessel 76 (ethyl acetate/water);
Experiment 1, vessel 79 (dichloromethane/water).
[0142] Polymorph C was for example detected in Experiment 2 vessel
46 (water); and Experiment 3 vessel 46 (water). Examination of IR
spectra from other areas of property space revealed absorption
bands of different wavelengths than those reported in the
literature. These strongly suggest the formation of novel
hydrates/polymorphs hitherto unreported in the literature. The
invention described herein, therefore, extends to any novel
hydrate, polymorph or other material prepared as described
herein.
CONCLUSION
[0143] Examination of property space as described in the above
experiments illustrates the ability to form different physical
forms/hydrates in differing areas of property space as defined.
[0144] The investigation apparatus can be used for investigating
the separation of diastereomers of a particular compound. In this
regard, it is known that diastereomeric salts of individual
compounds may have different crystallisation properties in certain
solvents. So the apparatus is used to investigate, for a particular
compound, which diastereomeric salts can be prepared which are
differentially crystallisable in particular solvents, thereby to
enable the selection of optimum conditions/reagents for separating
the isomers in a commercial preparatory process.
[0145] By way of example, if an active ingredient is known to be an
acid, then the variables that may be defined for investigation by
the apparatus include: [0146] B(i) formulation of different
salts--various different amines may be used to prepare different
diastereomeric salts of the active ingredient; [0147] B(ii) solvent
variables--the variables described in A(i) above may be used to
investigate whether the amine salts prepared in B(i) are
differentially crystallisable; and [0148] B(iii) the
heating/cooling profiles, stirring rates and total time as
described in A(ii), (iii) and (iv).
[0149] The apparatus may be used for investigating differentially
crystallisable diastereomeric salts in a similar manner to that
described above for assessing polymorphs. In this regard, the
variables described under point B(i) to (iii) for each reactor
device are programmed into the computer. After the computer has
been programmed, a measured amount of the optically active
ingredient to be assessed is introduced into the reactor devices.
The robot then delivers various predetermined amines and any other
required reagents to the devices to prepare desired salts of the
active ingredient. It should be appreciated that reagents or
solvents used in the preparation may be washed from the salt
prepared according to a predetermined process controlled by the
computer which may involve delivery of wash solvents by the robot
and/or removal of the nitrogen pressure and/or application of a
vacuum to separate undesired reagents/solvents from the salt
formed.
[0150] After the salt has been formed, it may be investigated by
re-crystallisation from a predetermined range of solvents under
predetermined conditions. After completion of the
re-crystallisation process, the nitrogen pressure is removed and
the vacuum applied to withdraw mother liquid or supernatant into
the sample vessels 15. The crystallised material on the frits
and/or the fluid collected in the vessels 15 may be analysed. As
will be appreciated, collection of a high level of one diastereomer
in one sample vessel 15 implies that the other diastereomer is
crystallisable and, therefore, present on the frits of the
associated reactor device. It will also be appreciated that the
analysis undertaken should show which combination of amine(s) and
solvent(s) and/or which physical conditions (e.g. temperature
profile, time, etc) allow optimum resolution of the diastereomeric
active ingredient.
[0151] The investigation apparatus may also be used for
investigating suitable salt forms in which an active ingredient,
such as a drug, may be delivered. By way of example, the variables
that may be defined for investigation include: [0152] (i) formation
of different salts--various different compounds (e.g. acids or
bases) may be used to prepare different salts; [0153] (ii) solvent
variables--the variables described in A(i) above may be used to
investigate whether the salts prepared are crystallisable from
various solvents; [0154] (iii) variables used to investigate
whether polymorphs of the different salts exist, e.g. using the
variables described in A(i) to (iv).
[0155] The apparatus may be used to assess suitable salt forms as
described above. Salts prepared may be assessed for polymorph
formation and other important properties such as melting point,
crystallinity, stability, hygroscopicity, solubility, level of
hydration, toxicity etc. may be analysed. Suitably, relevant
analytical information is input into the computer which is
programmed to analyse which are the best salts for further
investigation and/or to provide feedback on possible further
experimental investigations to be undertaken.
[0156] The reader's attention is directed to all papers and
documents which are filed concurrently with or previous to this
specification in connection with this application and which are
open to public inspection with this specification, and the contents
of all such papers and documents are incorporated herein by
reference.
[0157] All of the features disclosed in this specification
(including any accompanying claims, abstract and drawings), and/or
all of the steps of any method or process so disclosed, may be
combined in any combination, except combinations where at least
some of such features and/or steps are mutually exclusive.
[0158] Each feature disclosed in this specification (including any
accompanying claims, abstract and drawings), may be replaced by
alternative features serving the same, equivalent or similar
purpose, unless expressly stated otherwise. Thus, unless expressly
stated otherwise, each feature disclosed is one example only of a
generic series of equivalent or similar features.
[0159] The invention is not restricted to the details of the
foregoing embodiment(s). The invention extend to any novel one, or
any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
* * * * *