U.S. patent application number 12/970885 was filed with the patent office on 2011-04-14 for process for the controlled production of organic particles.
Invention is credited to Jian Feng Chen, Sung Lai Jimmy YUN.
Application Number | 20110087009 12/970885 |
Document ID | / |
Family ID | 20430764 |
Filed Date | 2011-04-14 |
United States Patent
Application |
20110087009 |
Kind Code |
A1 |
YUN; Sung Lai Jimmy ; et
al. |
April 14, 2011 |
PROCESS FOR THE CONTROLLED PRODUCTION OF ORGANIC PARTICLES
Abstract
A process for the production of a microparticle or a
nanoparticle of a chemical compound comprising the steps of
providing a solution of said chemical compound in a first liquid;
providing a second liquid in which said chemical compound is
insoluble or substantially insoluble; combining said liquids in a
region of high shear thereby causing formation of said particles;
and isolating said particles of said compound. The processing time
of a coacervation style process can be reduced and the yield can be
substantially increased both by control of the precipitation step
which allows for desolvation step to be dispensed with leading to
significant process time reduction. The invention also provides a
molecular mixing unit comprising an outer body defining a mixing
zone; a shear means to provide shear liquid in said mixing zone; at
least one fluid inlet means for a first liquid; at least one fluid
inlet means for a second liquid and a fluid outlet means.
Inventors: |
YUN; Sung Lai Jimmy; (Faber
Heights, SG) ; Chen; Jian Feng; (Faber Heights,
SG) |
Family ID: |
20430764 |
Appl. No.: |
12/970885 |
Filed: |
December 16, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10477386 |
May 17, 2004 |
7875295 |
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PCT/SG02/00061 |
Apr 15, 2002 |
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12970885 |
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Current U.S.
Class: |
530/364 ;
366/173.1; 560/71; 977/895 |
Current CPC
Class: |
B01J 13/04 20130101;
B01J 13/10 20130101; A61K 9/14 20130101 |
Class at
Publication: |
530/364 ; 560/71;
366/173.1; 977/895 |
International
Class: |
C07K 1/14 20060101
C07K001/14; C07C 67/48 20060101 C07C067/48; B01F 15/02 20060101
B01F015/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 9, 2001 |
SG |
200102700-2 |
Claims
1. A process for the production of a microparticle or a
nanoparticle of a chemical compound comprising: (a) providing a
solution of said chemical compound in a first liquid (b) providing
a second liquid in which said chemical compound is insoluble or
substantially insoluble; (c) combining said liquids in a region of
high shear thereby causing formation of said particles; and (d)
isolating said particles of said compound.
2. A process according to claim 1 wherein said step (c) comprises
injecting said liquids into a mixing zone comprising a shear means
which imparts high shear to said liquids.
3. A process according to claim 2 wherein said liquids are injected
into said mixing zone directly onto said shear means.
4. A process according to claim 3 wherein said shear means is
rotating in said mixing region to impart high shear to said
injected liquids.
5. A process according to claim 4 wherein said shear means is
rotating at a speed of from about 1,000 rpm to about 10,000
rpm.
6. A process according to claim 2 wherein said first liquid is
water.
7. A process according to claim 6 wherein said second liquid is
ethanol.
8. A process according to claim 7 wherein said ratio of said first
liquid to said second liquid injected into said mixing region is
0.8:1 to 1.2:1.
9. A process according to claim 4 wherein said shearing means is a
molecular packing.
10. A process according to claim 9 wherein said molecular packing
is a substantially cylindrical shear means formed from at least one
mesh layer.
11. A process according to claim 10 wherein said molecular packing
is formed from a plurality of overlapping mesh layers.
12. A process according to claim 10 wherein said molecular packing
is formed by rolling a mesh to form a substantially cylindrical
shear means wherein said cylindrical section is defined by sides
with a plurality of overlapping mesh layers.
13. A process according to claim 10 wherein said mesh has a mesh
size of 0.5 to 3.0 mm.
14. A process according to claim 13 wherein said mesh has a mesh
size of 0.1 to 0.5 mm.
15. A process according to claim 10 wherein said mesh has a
porosity of greater than 90%.
16. A process according to claim 15 wherein said mesh has a
porosity of greater than 95%.
17. A process according to claim 2 wherein each of said liquids are
injected into said mixing zone through a plurality of inlets.
18. A process according to claim 17 wherein each inlet for said
first liquid is located within said mixing region no further than
15 degree of arc from an inlet for said second liquid.
19. A process according to claim 3 wherein said injection velocity
of said injected liquids is greater than 1 ms.sup.-1.
20. A molecular mixing unit comprising: (a) an outer body defining
a mixing zone; (b) a shear means to provide shear liquid in said
mixing zone; (c) at least one fluid inlet means for a first liquid;
(d) at least one fluid inlet means for a second liquid; (e) a fluid
outlet means.
Description
FIELD OF INVENTION
[0001] In general this invention relates to a process for the
controlled production or organic micro-particles or nanoparticles
which are useful in pharmaceutical applications and an apparatus
for producing the same. In particular the present invention relates
to a process and an apparatus for the production of organic drug
particles of the nanoparticles size. These particles have been
found to be in particularly useful in the pharmaceutical industry
as nanoparticles have useful drug release properties which in many
applications are found to be superior to larger particles.
BACKGROUND OF THE INVENTION
[0002] The control of drug particle size is an important factor to
be considered when producing a pharmaceutical formulation
containing a solid active agent. For example, in certain
applications microparticles preferred whereas nanoparticles are
preferred for other applications.
[0003] Nanoparticles for example have found increasing use in the
pharmaceutical industry in recent years due to the inherent
properties brought about by their high surface area to volume
ratio. Accordingly, the ability of drug manufacturers to produce
such fine drug powders for use in formulations with controlled
particle size distribution has been an area of significant interest
to in the pharmaceutical industry. Indeed a significant amount of
the growth in the use of nanoparticles is due to the fact that the
particle size distribution of the active ingredient in drug
formulations has been found to have a direct influence on the
release properties of the drug upon administration (especially oral
administration).
[0004] In recent years, therefore, in addition to the interest in
controlling drug particle size there has been significant interest
in reducing the size of drug powders from the conventional
micron-size range to the nano-size range in order to take advantage
of this property. In addition, nanonization of pharmaceutical
powders has been found to be beneficial for and applicable to a
wide variety of drug delivery methodologies, such as colloidal,
intravenous injection, inhalation, and oral drug delivery
systems.
[0005] One example of such an application is that it has been found
that reducing the particle size of a drug can enhance the
dissolution of the drug into the biological environment. Thus it
has been found that the chiral nonsteroidal anti-inflammatory drug,
racemic ibuprofen--(often prescribed to treat arthritis, fevers,
menstrual symptoms, and pain)--has a poor dissolution rate in
water. Accordingly, improving its effectiveness in terms of
increasing the dissolution rate in the biological environment can
minimize the required intake of the drug by the patient. This in
turn minimises both the cost to the patient and the chance of
undesired side effects developing. This can be achieved by
increasing the available surface area of ibuprofen (which is
exposed to the biological environment) through reduction of the
particle size from the micrometer to the nanometer range.
[0006] Reduction in particle size can also improve the penetration
and dosage control of inhalation drug formulations. The lung tissue
of a patient is an effective media for drug delivery owing to its
large surface area. Insulin, for example, has been shown to be
effectively transported by means of inhalation as early as the
1970s. This mode of transport is particularly desirable to diabetes
sufferers as it can provide an alternative to daily multiple
subcutaneous injections which can be undesirable. The use of
nanoparticles in these applications is beneficial as nanoparticles
are easier for the patient to inhale and, in addition, are less
likely to cause irritation to the respiratory tract.
[0007] The benefits of being able to control drug particles size
and in particular to control drug particles in the nanoparticle
range is therefore manifest. There is therefore a need to develop
improved me methods to produce nanoparticles suitable for drug
delivery applications.
[0008] One technique for the preparation of nanoparticles which has
been used for protein particles is coacervation, which is the
controlled desolvation from a solvent system. In comparison to the
suspension cross-linking method, coacervation is considerably
simpler. In the coacervation method, the solute is first dissolved
into a solvent with or without the presence of a stabilizing agent
(for example albumin in aqueous solution), then a coacervation
agent (for example, ethanol) is added to the protein containing
solution, with constant stirring, to precipitate the protein and
form a suspension. The coacervation agent is subsequently
evaporated from the suspension by heating the suspension slowly
over an extended period of time (usually over 24 hours). As the
coacervation agent slowly evaporates from the suspension, the
precipitate will start to be re-dissolved back into the solvent,
reducing the particle size of the remaining precipitate during the
course of the desolvation process. It can therefore be seen that
controlling the desolvation process can control the size of the
particles produced leading to a number of particle sizes being
achievable.
[0009] Unfortunately, the coacervation method suffers not only from
the lengthy processing time required but also provides a low
process yield as a significant amount of the desired solute is
re-dissolved back into the solvent prior to the desired particle
size being achieved. Whilst the material obtained can be
re-subjected to the process this requires further time and energy
input. In addition, the precipitate that is formed tends to be
unstable and form aggregates which are undesirable from and
end-user standpoint. It is clear therefore that viable
alternatives/improvements to this method are required.
INFORMATION DISCLOSURE
[0010] U.S. Pat. No. 6,007,791 in the name of Chiron Corporation
describes a process of preparing microspheres, films and coatings
from proteins or modified proteins in the protein product is
stabilized stabilized by carrying out the preparation of the
microspheres in the presence of an aqueous solution of at least one
.alpha.-hydroxy acid. This uses the .alpha.-hydroxy acid as a
stabilising agent for the microspheres. The methods of coacervation
described in this practice standard coacervation methodology with
aqueous solution of the protein to be converted into a microsphere
with a coacervation agent stirring the mixture to form
microspheres. The difficulty with such a process is as noted that
microspheres produced normally in the 10-50 micrometer range and
instead of the nanometer range.
[0011] U.S. Pat. No. 5,879,715 in the name of CeraMem Corporation
relates o a process for the production of inorganic nanoparticles
by precipitating the inorganic nanoparticles by a precipitating
agent from a microemulsion with a continuous and a non-continuous
phase; and concentrating the precipitated nanoparticles employing
an ultrafiltration membrane. In essence this technology utilises
standard coacervation techniques.
[0012] U.S. Pat. No. 5,916,596 in the name of Vivorx
Pharmaceuticals, Inc. relates to a process for producing
nanoparticles using standard coacervation techniques wherein the
particle size is controlled by careful solvent selection and
preparation conditions. There is no teaching in this document of
the use of high shear in the coacervation step leads to control
particle size.
[0013] U.S. Pat. No. 5,874,029 in the name of The University of
Kansas describes production of microparticles and nanoparticles in
which a compressed fluid and a solution including a solvent and a
solute are introduced into a nozzle to produce a mixture. The
mixture is then passed out of the nozzle to produce a spray of
atomized droplets. The atomized droplets are then contacted with a
supercritical antisolvent to cause depletion of the solvent in the
droplets so that the particles are produced from the solute.
Preferably, these particles have an average diameter of 0.6 .mu.m
or less. This therefore relies on a spraying type vaporisation
process.
[0014] Whilst all these prior art documents relate to coacervation
or a variation thereof, they all control the particle size by
standard coacervation technology such as judicious solvent
selection and/or other physical steps. It is typically found that
these variables are very compound specific and therefore the
methods disclosed are not methods that can be utilised for all
compounds. In addition, as noted above, many of these compounds or
methods only produce microparticles and do not produce particles in
the nanoparticle range.
[0015] In the present invention, a novel technique has been
developed to reduce to the processing time of a coacervation style
process and, in addition, substantially increase the yield. This
has been achieved in the present process by control of the
precipitation step which allows for the desolvation step to be
dispensed with leading to significant process time reduction. In
addition, utilising the present process it is typically found that
higher process yields are obtained.
SUMMARY OF INVENTION
[0016] In one aspect the present invention provides a process for
the production of a microparticle or a nanoparticle of a chemical
compound comprising:
[0017] (a) providing a solution of said chemical compound in a
first liquid;
[0018] (b) providing a second liquid in which said chemical
compound is insoluble or substantially insoluble;
[0019] (c) combining said liquids in a region of high shear thereby
causing formation of said particles; and
[0020] (d) isolating said particles of said compound.
[0021] Preferably the process of combined the liquids in a region
of high shear is achieved by injecting said liquids into a mixing
zone containing a shear means. Preferably the injection is carried
out at a high injection velocity of >1 ms.sup.-1 more so
preferably >3 ms.sup.-1 most preferably >5 ms.sup.-1. It is
also preferred that the high shear is provided by rapid rotation of
the shear means in the mixing zone leading to shearing of liquids
in said mixing zone.
[0022] In yet a further aspect the invention provides a molecular
mixing unit comprising:
[0023] (a) an outer body defining a mixing zone;
[0024] (b) a shear means to provide shear to said mixing zone;
[0025] (c) at least one fluid inlet means for a first liquid;
[0026] (d) at least one fluid inlet means for a second liquid;
[0027] (e) a fluid outlet means.
[0028] By the use of this unit the precipitation step can be
controlled as the unit allows control of the step of adding the
coacervation agent (second liquid) to the solute-laden solvent
(first liquid) to control the nucleation and particle growth. The
particle size can be controlled in either micron or nano size
region by adjusting the rotational speed of the shear means in the
mixing zone, by different structural features of the shear means
and injecting shear of first and second liquids into the mixing
zone at different rates of injection.
DETAILED DESCRIPTION OF THE FIGURES
[0029] FIG. 1--This figure shows the particle size distribution
obtained for the particles produced in example 1.
[0030] FIG. 2--This figure shows the particle size distribution
obtained for the particles produced in example 2.
[0031] FIG. 3--This figure shows the particle size distribution
obtained for the particles produced in example 3.
[0032] FIG. 4--This figure shows the particle size distribution
obtained for the particles produced in example 4.
[0033] FIG. 5--This is a diagram showing one embodiment of the
molecular mixing unit of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0034] As used herein nanoparticles mean particles having an
average particle size of less than 100 nanometers.
[0035] As used herein microparticles mean particles having an
average particle size of less than 100 micrometres.
[0036] As used herein nanonization means the process of reducing
the particles to be in a range such that the average particle size
is less than 1000 nanometers in size preferably less than 100
nanometers in size.
[0037] In conventional coacervation methods, high speed stirring is
used to disperse the precipitate that is formed during the mixing
of the coacervation agent and solvent. It has been found, however,
that stirring on its own has little or no control on the nucleation
and the growth of the particles during the precipitation process.
Accordingly, particles formed during the initial precipitation in
conventional coacervation methods are typically large and
irregular, and subsequently, require a lengthy desolvation step to
reduce the size of the particle to the desired nanoparticle
range.
[0038] After significant research the present inventors have found
that if during the precipitation step the fluids are subject to a
shearing means to impart sufficiently high shear to the liquids
either as they are combined or immediately thereafter the particle
size can be controlled. Whilst not wishing to be bound by theory it
is thought subjection of the liquids to high shear leads to
improved interaction between the two liquids leading to faster
precipitation of the desired compound caused by the mixing. This is
thought to occur as the high shear breaks the two liquids up into
smaller particles and leads to more intimate mixing between the two
liquids and hence more homogeneous precipitation of the drug
particles. This thus increases the rate at which the liquids
interact in turn increasing the speed of precipitation of the
chemical compound from solution. As will be clear to a skilled
addressee the quicker the homogeneous mixing of the two liquids and
the faster the precipitation process, the smaller and the more
uniform particles produced during precipitation will be.
[0039] Fast precipitation alone results in big particles and the
applicants have found that you need quick homogeneous mixing to
ensure that the shear will break up the liquid into nanosized
droplets, which in turn will result in the precipitation of a
nanosized particle. Once again, without wishing to be bound by
theory it is thought that in such precipitation reactions between
the two liquids all or substantially all the dissolved solid in a
drop of solvent will precipitate when brought into contact with a
precipitating solvent. Accordingly, following this theory the
smaller the droplets can be made when this occurs the smaller the
particles of drug formed will be. In addition it is expected that
the quicker the homogeneous mixing and the faster the precipitation
leads to a more uniform particle size distribution observed. This
of course will be clearly desirable as it ensures more uniformity
of activity of the drug in use.
[0040] In the process of the invention it is preferred that the
shearing means is a specially designed packing for mass transfer
enhancement and micromixing intensification. This use of a shearing
means significantly increases the intensity of micromixing between
the solvent and coacervation agent (first and second liquids),
therefore, controlling the nucleation and the growth of the
particles right from the start of the precipitation step. In many
cases, fine particles of less than 200 nm can be formed
instantaneously after the second liquid is added to the first
liquid with no further desolvation step required which
differentiates the present process from previous processes. This
therefore significantly reduces the processing time required and
increases the product yield. The process will now be discussed in
greater detail.
(a) Chemical Compounds
[0041] The process of the present invention can be utilised with a
number of chemical compounds. Indeed, in principle the process can
be carried out with any chemical compound however the compound must
be such that it is able to withstand subjection to the high shear
encountered in the process without degradation. As such some
polymeric compounds may not be amenable to the process of the
invention nor may some particularly sensitive long chain proteins.
It is expected, however that a skilled addressee would be quickly
able to determine the suitability of a compound to subjection to
the process. In addition, in order to be subjected to this process
the compound must be soluble in at least one solvent. This
restriction typically presents no problem as most compounds are
typically soluble in at least one solvent as would be clear to a
skilled addressee. It is preferred that the compound is an organic
compound particularly to an organic drug compound.
[0042] The compound used may preferably be selected from any one of
the following:
[0043] Antacids, antibiotics, anti-inflammatory substances,
coronary dilators, peripheral vasodilators, anti-infectives,
psychotropics, anti-manics, stimulants, anti-histamines, laxatives,
decongestants, vitamins, gastro-intestinal sedatives,
anti-diarrhoeal preparations, anti-anginal drugs, vasodilators,
anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and
migraine treatments, anti-coagulants and anti-thrombotic drugs,
analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics,
anti-nauseates, anti-convulsants, neuromuscular drugs, hyper- and
hypoglycaemic agents, thyroid and anti-thyroid preparations,
diuretics, anti-spasmodics, uterine relaxants, mineral and
nutritional additives, anti-obesity drugs, anabolic drugs,
erythropoietic drugs, anti-asthmatics, bronchodilators,
expectorants, cough suppressants, mucolytics, anti-ulcer and
anti-urecemic drugs;
[0044] Gastro-intestinal sedatives such as metoclopramide and
propantheline bromide, Antacids such as aluminium trisilicate,
aluminium hydroxide and cimetidine, Antibiotics such as cefradine
and amoxycillin;
[0045] Anti-inflammatory drugs such as phenylbutazone,
indomethicin, naproxen, ibuprofen, flurbiprofen, diclofenac,
dexamethasone, prednisone, and prednisone;
[0046] Coronary vasodilator drugs such as glyceryl trinitrate,
isosorbide dinitrate and pentaerythritol tetranitrate,
peripheral;
[0047] Cerebral vasodilators such as soloctidilum, vincamine,
naftidrofuryl oxalate, co-dergocrine mesylate, cylandelate,
papaverine and nicotine acid;
[0048] Anti-infective substances such as 1-Napthyl Salicylate,
erythromycin stearate, cephalexin, nalidixic acid, tetracycline
hydrochloride, ampicillin, flucloxacillin sodium, hexamine
mandelate hexamine hippurate, and amoxacylin vancomycin;
[0049] Neuroleptic drugs such as flurazepam, diasepam, temazepam,
amitryptyline, doxepin, lithium carbonate, lithium sulfate,
chlorpromazine, thioridazine, trifluperazine, fluphenazine,
piperothiazine, haloperidol, maprotiline hydrochloride, imipramine
and desmethylimipramine;
[0050] Central nervous stimulants such as methylphenidate,
ephedrine, epinephrine, isoproterenol, amphetamine sulfate and
amphetamine hydrochloride;
[0051] Antihistamic drugs such as diphenhydramine,
diphenylpyraline, chlorpheniramine and brompheniramine;
[0052] Anti-diarrheal drugs such as bisacodyl and magnesium
hydroxide, the laxative drug, dioctyl sodium sulfosuccinate;
[0053] Nutritional supplements such as ascorbic acid, alpha
tocopherol, thiamine and pyridoxine;
[0054] Anti-virals such as acyclovir;
[0055] Anti-spasmodic drugs such as dicyclomine and diphenoxylate,
drugs affecting the rhythm of the heart such as verapamil,
nifedipine, diltiazem, procainamide, disopyramide, bretylium
losylate, quinidine sulfate and quinidine gluconate;
[0056] Drugs used in the treatment of hypertension such as
propranolol hydrochloride, guanethidine monosulphate, methyldopa,
oxprenolol hydrochloride, captopril and hydralazine;
[0057] Drugs used in the migraine such as ergotamine;
[0058] Drugs affecting coagulability of blood such as epsilon
aminocaproic acid and protamine sulfate;
[0059] Analgesic drugs such as acetylsalicylic acid, acetaminophen,
codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine
tartrate, oxycodeinone, morphine, heron, nalbuphine, butorphanol
tartrate, pentazocine hydrochloride, cyclazacine, pethidine,
buprenorphine, scopolamine and mefenamic acid;
[0060] Anti-epileptic drugs such as phenytoin sodium and sodium
valproate;
[0061] Neuromuscular drugs such as dantrolene sodium;
[0062] Substances used in the treatment of diabetes such as
tolbutamide, disbenase glucagon insulin and metformin;
[0063] Drugs used in the treatment of thyroid gland disfunction
such as triiodothyronine, thyroxine and propylthiouracil;
[0064] Diuretic drugs such as furosemide, chlorthalidone,
hydrochlorthiazide, spironolactone and trimterone, the uterine
relaxant drug ritodrine;
[0065] Appetite suppressants such as fenfluramine hydrochloride,
phentermine and diethylproprion hydrochloride;
[0066] Anti-asthmatic and bronchodilator drugs such as
aminophylline, theophylline, salbutamol, orciprenaline sulphate and
terbutaline sulphate;
[0067] Expectorant drugs such as guaiphenesin, cough suppressants
such as dextromethorphan and noscapine;
[0068] Mucolytic drugs such as carbocisteine;
[0069] Anti-septics such as cetylpyridinium chloride, tyrothricin
and chlorohexidine;
[0070] Decongestant drugs such as phenylpropanolamine and
pseudoephedrine, hypnotic drugs such as dichloralphenazone and
nitrazepam;
[0071] Anti-nauseant drugs such as promethazine theoclate;
[0072] Haemopoietic drugs such as ferrous sulphate, folic acid and
calcium gluconate; and
[0073] Uricosuric drugs such as sulphinpyrazone, allopurinol and
probenecid. The choice of chemical compound to be converted to a
particle will determine the first and second liquids to be used in
the process of the invention.
(b) First and Second Liquids
[0074] The selection of first and second liquids is a very
important step in the process of the invention. The first and
second liquids can be single solvents or mixtures of solvents
however there are a number of features that the liquids must have
in order to successfully practice the invention. It is important
for example, that the first liquid is one in which the compound to
be converted to a particle is soluble. Whilst this will clearly
vary depending on the particular compound the choice of a first
liquid will typically not cause difficulty for a skilled addressee
as the solubility can be determined easily by trial and error. It
is particularly preferred that the first solvent is water as this
is most environmentally friendly and cost effective.
[0075] Once the first liquid has been selected the compound is then
dissolved in the liquid. In principle the amount of first liquid
used is irrelevant as long as there is an adequate amount to fully
dissolve the compound to provide a solution of the compound in the
first liquid. In practical terms, however, for the purposes of
economy it is found that the amount of first solvent should be no
more than is necessary to just dissolve the compound (ie just
enough to produce a saturated solution of the compound in the first
liquid). It is found that if an excess of liquid is used the yield
of recovered particles from the process of the invention is lower
and/or a larger amount of second liquid is required to achieve a
comparable yield. In both instances from an economic standpoint
this is undesirable and therefore excess amounts of the first
liquid should be avoided where possible.
[0076] The second liquid should generally be chosen such that the
compound to be converted to a particle is insoluble or
substantially insoluble in the second liquid. Alternatively the
second liquid is chosen so that it is one in which when it is
brought into contact with a solution of the compound in the first
liquid leads to precipitation of the chemical compound from
solution. It is preferable that the second liquid is miscible with
the first liquid although this need not be the case. It is
particularly preferred that the second liquid is ethanol.
[0077] The ratio of first liquid to second liquid used in the
process of the invention can vary greatly although it is preferred
that the ratio is near to one. Accordingly in a preferred ratio the
first and second liquids are utilised in a ratio of from 10:1 to
1:10, more preferably 4:1 to 1:4, even more preferably from 3:1 to
1:3, yet even more preferably from 0.8:1 to 1.2:1.0, most
preferably 1:1. The exact ratio will depend on the chemical
compound selected and the liquids chosen. A skilled addressee will
understand that any number of ratios will work successfully for any
given combination of chemical compound, first and second
liquid.
(c) Formation of an Intimate Mixture
[0078] Once the liquids have been chosen they are combined in a
region of high shear to form an intimate mixture of the two liquids
thereby causing precipitation of particles of the compound from the
mixture. A preferred method of combining the liquids is to inject
them into a mixing zone containing a shear means. In a particularly
preferred embodiment the shear means is rotating in the mixing zone
and said first and said second liquids are injected directly onto
the rotating shear means.
[0079] Preferably the liquids are injected simultaneously through
separate inlets. In an even more preferred embodiment the liquids
are each injected via a plurality of inlets. The inlets can be
located either around the outside of the mixing zone or are located
on as to deliver the liquids to the centre of the mixing zone. In a
particularly preferred embodiment the liquids are injected through
a distributor located in the centre of the mixing region surrounded
by the rotating shear means. The injection velocity of the liquid
(flow velocity as it exists from the inlet) is preferably greater 1
ms.sup.-1, more preferably greater than 3 ms.sup.-1 and most
preferably greater than 5 ms.sup.-1.
(d) Shear
[0080] The process involves the use of a shear means to impart high
shear to the two liquids in the mixing zone. This has the advantage
that the two liquids are adequately mixed to form an intimate
mixture leading to the formation of a precipitate of the desired
size. The shear means is preferably a packing with a surface area
of 200-3000 m.sup.2/m.sup.3. The packing can be such that it is
structured packing or random packing. A preferred packing is a
packing of the wire mesh type packing that can be made from either
stainless steel, plain metal alloy, titanium metal or plastic. It
is preferred that the packing is a substantially cylindrical shear
means formed from at least one mesh layer. More preferably it is
formed from a plurality of overlapping mesh layers. In a most
preferred embodiment the shear means is formed by rolling mesh to
form a cylindrical shear means wherein the cylindrical section has
sides formed by a plurality of overlapping mesh layers. If it is
used it is preferred that the mesh has a mesh size of 0.05 to 3 mm,
more preferably 0.1 to 0.5 mm. The mesh has a preferred mesh
porosity of at least 90%, preferably more than 95%.
[0081] In a particularly preferred embodiment the shear means is
mounted on a shaft in the mixing zone and rotates in the mixing
zone. In a particularly preferred embodiment the shear means is a
cylindrical shape and defines a hollow to accommodate the inlets
for the liquids. It will be appreciated, however, that the shape of
the container in which the two liquids are combined can also be
used to impart shear to the liquids.
[0082] As discussed about it is preferred that the shear means
rotates in said mixing zone at a sufficient speed to input high
shear to said liquids in said zones. The rotation speed is
typically of the order of 100 to 15000 rpm, preferably 500 to 12000
rpm, even most preferably 5000 to 8000 rpm. The use of such a
strong rotation of the shear means ensures that the two liquids in
the mixing zone are subjected to strong shear immediately upon
injection.
[0083] In the process of the invention it is preferred that the
liquids are injected into the mixing region by way of a liquid
distributor located in the centre of the mixing region in a hollow
defined by the rotating shear means. It is preferred that the
liquids are injected directly onto the shear means and have an
injection speed of at least 1 ms.sup.-1, more preferably at least 3
ms.sup.-1, most preferably at least 5 ms.sup.-1. It is preferred
that each of the liquids is injected through a plurality of the
inlets. It is preferred that each inlet for the first inlet is
spaced no further than 15.degree. of are from an inlet for the
second outlet.
(e) Isolation
[0084] Once the liquids have been mixed and the particles produced
the mixture is discharged from the mixing zone and the particles
isolated. If the process is carried out as a continuous process
which is preferred the addressed liquids are constantly being
withdrawn from the mixing zone and the solid isolated. The
particles may be isolated by filtration, centrifugation or any
other method of isolation of a solid from a liquid. It is preferred
that the solid is isolated by filtration.
[0085] A variety of drug and organic nanoparticles can be prepared
using the above method, In addition, the active ingredients can
also be co-precipitated with polymer to form drug encapsulated
polymer nanospheres or microspheres. Examples of polymers that can
be used in this way are Polyisobutylcyanoacrylate (PIBCA), (2)
Polyisohexlcyanoacrylate (PHICA), Poly (D-L lactic acid) (PLA) and
Polystyrene (PS).
[0086] In the embodiment described above the process has been
described as a continuous process in a specific reaction vessel. It
is to be understood, however, that the process could be carried out
in a continuous fashion using a pipe means as the reactor. For
example the process could be such that the shear means is located
in a pipe and the two fluids are injected into the pipe with the
pressure of the liquids forcing the combined liquids through the
shear means located in the pipe. The amount of shear could be
controlled by the number of shear devices/means located in the pipe
and the residence time of the liquids in the area of shear. In the
method there would be no requirement to rotate the shear means.
Description of the Molecular Mixing Unit
[0087] In yet a further aspect, the invention provides a molecular
mixing unit comprising:
[0088] (a) an outer body defining a mixing zone;
[0089] (b) a shear means to provide shear liquids in said mixing
zone;
[0090] (c) at least one fluid inlet means for a first liquid;
[0091] (d) at least one fluid inlet means for a second liquid;
[0092] (e) a fluid outlet means.
[0093] The outer body of the molecular mixing unit can be made of a
number of materials. It is preferred that the body is made of
stainless steel. The body is designed such that it defines a mixing
zone. The mixing zone can in theory be any of a number of sizes and
the size chosen will depend of the rate of the process to be
carried out and the amount of material to be processed.
[0094] The mixing zone is provided with a shear means located
within said mixing zone to impart high shear to said liquids
injected into said mixing zone. In principal, the shear means can
be any device which imparts high shear on fluid. In the preferred
embodiment the shear means is a molecular packing with a surface
area of 200 to 3000 m.sup.2/m.sup.3. The packing can be either
structured packing or random packing with structured packing being
particularly preferred. The preferred packing is packing of wire
mesh type that can be made of either stainless steel, plain metal
alloy, titanium or plastic. It is preferred that the packing is a
substantially cylindrical shear means formed from at least one mesh
layer. More preferably it is formed from a plurality of overlapping
mesh layers. In a most preferred embodiment the shear means is
formed by rolling mesh to form a cylindrical shear means wherein
the cylindrical section has sides formed by a plurality of
overlapping mesh layers. It is preferred that the mesh of this
packing has a mesh size of 0.05 to 3 mm, preferably 0.1 to 0.5
mm.
[0095] In a particularly preferred embodiment of the invention the
shear means is a molecular packing attached to a rotating means
located in said mixing zone to rotate said shear means in the
mixing region. In such an embodiment as the rotating means rotates
said packing rotates imparting high shear onto the injected
liquids. It is preferred that said shear means also defines a
hollow into which the liquid inlets can be located. Whilst not
wishing to be bound by theory it is felt that the use of a high
shear device in the unit breaks the solution into discrete
particles of the two liquids leading to high surface area contact
between them leading to the fast precipitation and formation of the
desired particles.
[0096] It is found to be particularly efficient if the two liquids
are injected into the mixing zone via separate fluid inlets.
Accordingly, preferably the molecular mixing device has at least
one fluid inlet for fluid inflow of each of the first and second
liquids respectively. Preferably there are a plurality of inlets
for each liquid. Of course, these liquid inlets may be arranged in
a number of ways depending on the structural design of the mixer.
It is preferred that the liquid inlets are located in a distributor
which preferably is located in the hollow defined by said shear
means. Preferably the distributor defines a plurality of inlets for
each of the first and second liquids. In a most preferred
embodiment the liquid inlets alternate on the distributor.
[0097] In addition, there should be at least one liquid outlet
means for draining the molecular mixing device either in a
batchwise or continuous fashion. The molecular mixing device will
now be described in greater detail with reference to the attached
FIG. 5.
[0098] In the FIG. 5 the outer shell of a molecular mixing unit is
shown (5). The outer shell shown here includes a gas blanket shown
as gas-in and gas-out in order to isolate the reaction process from
the oxygen environment. Whilst this is shown in a Figure this is
merely a preferred embodiment as gas blanketing will not be
required for a number of compounds. The first and second liquids
are located separately in the solution chambers (1). For a typical
run, one of the liquids would be located into chamber (1) on the
left of the drawing and the other liquid would be located in
solution chamber (1) on the right. These solutions are then pumped
through pumps (2) to flow metres (4) through pipes into a
distributor (6) located within the mixing chamber. This distributor
is located within a hollow created by the shear means (7). The
shear means is a cylindrical shear means which surrounds the
distributor (6) forming a hollow in which the distributor sits.
Shear means (7) is shown attached to shaft which in turn is
attached to motor (3) in order to rotate the shear means within the
mixing zones. In use the solutions are pumped in through the
distributor in the mixing zone onto the rotating shear device. As
will be understood by a skilled addressee there are a number of
ways in which the liquids can be injected into the mixing zone and
the one shown in this figure is merely a preferred embodiment. The
number of inlet points for each liquid and the size and shape of
the inlet points would depend on the compounds chosen and may vary
greatly. The pump is rated so that the velocity of liquid pumped
into mixing chamber through the inlet points should preferably be
in the range of 1 ms.sup.-1, more preferably at least 3 ms.sup.-1,
and most preferably greater than 5 ms.sup.-1.
[0099] As will be appreciated by also a skilled addressee after a
series of long processing, the packing may be clogged. As would be
understood this can be easily remedied by washing with solvent
materials and or by cleaning the packing dye by using conventional
clean-in place solvent procedures.
[0100] The invention will now be described with reference to the
following examples.
EXAMPLE 1
Preparation of 1-Napthyl Salicylate (NAS) Nanoparticles by the
Molecular Mixing Method
[0101] A 5% by weight NAS was dissolved in ethanol. The second
liquid used was water. Water and the NAS/ethanol solution were
injected into the molecular mixing unit continuously at a
volumetric flow rate of 5 volume of water to 1 volume of
NAS/ethanol solution. The two solutions were injected directly into
the high speed rotational packing located inside the molecular
mixing unit. The rotational speed was set at 10,000 rpm. The
nanoparticles were recovered by sterile-filer and vacuum dried (it
can also be freeze dried, spray dryer, flash dryer).
[0102] The particle size of the nanoparticles was analyzed by the
PCS (Photon Correlation Spectrum, Particle Sizer, Malvern, UK) and
was found to be 25.1 nm as shown in FIG. 1.
EXAMPLE 2
[0103] Same conditions as example 1 with the exception of
rotational speed being reduced to 2500 rpm.
[0104] The particle size of the nanoparticles was analyzed by PCS
and was found to be 82.3 nm as shown in FIG. 2.
EXAMPLE 3
Preparation of BSA Nanoparticles by the Molecular Mixing Method
[0105] A 5% by weight BSA aqueous solution was prepared. The second
liquid used was ethanol. Ethanol and the BSA solution were injected
into the molecular mixing unit continuously at a volumetric flow
rate of 3 volume of ethanol to 1 volume of BSA solution. The two
solutions were injected directly into the high speed rotational
packing located inside the molecular mixing unit. The rotational
speed was set at 5000 rpm. The nanoparticles were recovered by
sterile-filer and vacuum dried (it can also be freeze dried, spray
dryer, flash dryer).
[0106] The particle size of the nanoparticles was analyzed by PCS
and was found to be 151 nm as shown in FIG. 3.
EXAMPLE 4
[0107] Same condition as example 3 with the exception of
solvent:anti-solvention volume ratio being reduced to 1:2.
[0108] The particle size of the nanoparticles was analyzed by PCS
and was found to be 400.9 nm as shown in FIG. 4.
* * * * *