AU783570B2 - Coformulation methods and their products - Google Patents

Description

WO 01/15664 PCT/GB00/03328 Coformulation Methods and their Products This invention relates to methods for coformulating an active substance and an oligomeric or polymeric excipient. It also relates to the particulate products of such methods.

In particular, it relates to new applications and products of the particle formation technique known as SEDSM (Solution Enhanced Dispersion by Supercritical fluids), which is described in WO-95/01221 and (in modified versions) in WO-96/00610, WO- 98/36825, WO-99/44733 and WO-99/59710. It has been found that this technique may be used to produce novel coformulation products, especially of pharmaceutically active ingredients with oligomer or polymer excipients, having advantageous physicochemical characteristics.

It is known to coformulate pharmaceuticals with polymers in order to modify their solubility profiles and hence, for example, improve the dissolution of an otherwise poorly soluble drug, or slow the dissolution of a highly soluble drug so as to control its release after administration or to reduce its toxicity.

Known techniques for preparing such drug/polymer coformulations include solvent evaporation and coprecipitation, from a mixture of the drug and polymer in a common solvent system. Such approaches are often limited however by manufacturing difficulties, including environmental constraints, solvent problems such as the need for multiple solvent systems and the consequent risk of phase separation, harvesting difficulties and the high levels of polymer often required. Other major limitations tend to be the poor physical properties and processing characteristics of the particulate products, which can be cohesive and difficult to handle, may contain unacceptable levels of residual solvent or non-uniform drug distributions, may suffer poor chemical and physical stability and are often large particles which need to be further reduced in size before they can be processed into commercial products. It can also be difficult to control the morphology of the drug in the system, ie, the relative proportions of its crystalline and (more soluble, and hence generally preferred) amorphous phases.

There is a tendency too for amorphous phase drugs, even in the presence of polymeric excipients, to be meta-stable with respect to the crystalline phase. Over extended storage periods an amorphous drug can revert to its crystalline form, with consequent changes in its dissolution profile. The degree of instability may depend on storage temperature (in particular with respect to the glass transition temperature, Tg, of the amorphous solid) and humidity, and on relative drug and excipient concentrations. It can also be affected to some degree by the choice of excipient, and even by the manner in which the drug/polymer mixture was prepared. (See references An active substance such as a drug should have stable characteristics under "normal" storage conditions, typically at room temperature and for shelf lives of at least two years. Thus for pharmaceuticals, standards are being developed which require stability for reasonable periods at 25C. Previous attempts to coformulate drugs with excipients have generally failed to achieve an amorphous phase active with such a high level of stability, in many cases recrystallisation has been observed within days, if not hours supra).

Matsumoto and Zografi claim more recently to have stabilised the amorphous phase of the drug indomethacin, using poly vinyl pyrrolidone (PVP) as an excipient. They report storage periods of up to 20 weeks at 30 0 C without recrystallisation, for coformulations containing up to 95% indomethacin. The properties of the system are explained in terms of hydrogen bonding between the drug and polymer, which disrupts the drug dimers associated with the crystalline phase.

The products of the present invention are coformulations of an active substance, 20 typically a pharmaceutically active substance, with an oligomeric or polymeric material.

They contain significant amounts of the active substance in its amorphous form, the a* stability of which can be much greater than in analogous prior art coformulations. They S: can be used in particular in the design and manufacture of drug delivery systems, to control drug release and/or enhance bioavailability.

According to a first aspect of the present invention, there is provided a coformulation of an active (preferably a pharmaceutically active) substance and an oligomeric or polymeric material other than poly vinyl pyrrolidone, containing at least 10 w/w of the active substance, in which between 90 and 100 w/w of the active substance is present in an amorphous as opposed to crystalline form, and wherein there is no detectable change in the amount of any crystalline form(s) I .30 of the active substance present in the coformulation for at least eighteen months following its preparation when the coformulation is stored at 25 0 C and up to 60 relative humidity, provided that S. when the active substance is paracetamol, the oligomeric or polymeric material is not L-PLA.

By "stable" is meant that, over the specified time period, there is no significant change in the X-ray diffraction (XRD) pattern of the coformulation and, where appropriate (ie, where measurable) in its differential scanning calorimetry (DSC) profile.

There is preferably no significant change in the dissolution profile of the coformulated active substance. In other words, there is little or no detectable change in the amount of any crystalline form(s) present after the specified time period, preferably less than more preferably less than most preferably less than 0.1% change with respect to the initial amount. Yet more preferably, the coformulation contains no detectable crystalline active substance both pre- and post-storage.

The amorphous phase active substance is stable for at least eighteen and, preferably, at least twenty four or thirty six months after its preparation.

It is stable, for the periods mentioned above, when stored at 25 0 C and up to RH. Even more preferably, it is stable when stored at 40 0 C, most preferably at 40 0 C and up to 75% RH.

A coformulation according to the invention is typically an intimate mixture of the active substance dispersed in a "matrix" of the oligomer or polymer excipient, in which the solubility characteristics of the active substance are modified due to the presence of the excipient. Usually the dissolution rate of the active substance will be enhanced by coformulating it, but in some cases (for instance of use in "controlled release" drug S formulations) it may be inhibited.

S. The products of the present invention, when made by a SEDSTM process, tend .'.not only to be more stable but also generally less cohesive, more free flowing (having discrete particles) and easier to handle and process, than analogous coformulations made according to more conventional methods (in particular prior art coformulations containing amorphous or even semi-crystalline actives, which can have extremely poor aO, *4 *p WO 01/15664 PCT/GB00/03328 handling properties). The products of the invention can also be made with particle sizes down to between 0.1 and 1 pm, with relatively narrow size distributions.

Another advantage of the products of the present invention is that they can generally be prepared in the absence of additional surfactants, which many prior art coformulations require as stabilisers. They also usually contain significantly reduced levels of residual solvents. Moreover, since they are precipitated rapidly from homogeneous active/excipient solutions, they tend to contain more uniform active distributions, a characteristic which is especially important when formulating low dosage drugs.

The coformulations of the invention are preferably prepared by a SEDS

T

process, from one or more "target solutions" containing the active substance and/or the oligomeric or polymeric material. It has been found that SEDSTM-coformulated products can contain higher levels of amorphous phase active than is often possible using prior art production methods, and more significantly that the amorphous phase is more stable, with respect to reversion to the crystalline phase, than in conventionally produced -coformulations. This may be due to increased intimacy of the active substancelexcipient mix, and/or to reduced levels of residual solvent, although we do not wish to be bound by these theories. It may also be the case that the SEDS T method involves such rapid particle formation that neither the drug nor the excipient molecules are able to group themselves with any degree of order as they precipitate. The slower prior art coformulation processes, such as solvent evaporation and spray drying, may result in the formation of"microdomains", small seed crystals that can act as nucleation sites for subsequent re-cystallisation. If a coformulation contains a significant number of such nucleation "seeds", it will almost inevitably revert to the crystalline form on storage, often within a short period.

That SEDS T M may be used to prepare such coformulations is surprising in view of earlier literature on the process. In WO-95/01221, for example, there are examples of drug/polymer coformulations (salmeterol xinafoate and hydroxypropyl cellulose), but although these apparently demonstrate "disturbance" of crystallinity, it is clear from the appended DSC/XRD data that significant amounts of the crystalline drug are still present.

Elsewhere in WO-95/01221 and WO-96/00610, there is emphasis on the ability of

SEDS

T M to yield crystalline materials, and most of the examples in those documents and WO 01/15664 PCT/GB00/03328 in WO-98/36825, WO-99/44733 and WO-99/59710 show highly crystalline products when SEDS T M is used to process organic materials.

Thus, although SEDS T M is a fast precipitation process, which might otherwise have been expected to produce amorphous solids, in fact it has been shown to force the majority of organic compounds into a crystalline state. The addition of a polymer might be expected, as in Examples 10 and 16 ofWO-95/01221, to reduce crystallinity levels, but it would not be predicted to achieve 100% amorphous drug systems, particularly at the relatively high drug loadings now found to be possible (in the past, high levels of polymer or greater) tend to have been needed to give any significant reduction in crystallinity Moreover, the products of the invention have significantly improved long term stability (with respect to active re-crystallisation), which could not have been predicted from the prior art.

By "a SEDST M process" is meant a particle formation technique as described in WO-95/01221, WO-96/00610, WO-98/36825, WO-99/44733 and/or WO-99/59710, in which a supercritical or near-critical (preferably supercritical) fluid anti-solvent is used simultaneously both to disperse, and to extract a fluid vehicle from, a solution or suspension of a target substance. Such a technique can provide better, and more consistent, control over the physicochemical properties of the product (particle size and size distribution, particle morphology, etc.) than has proved possible for coformulations in the past.

SEDS

T is also a one-step process; it can be used to precipitate both the active substance and the excipient at the same time, either from the same or from separate "target" solutions or suspensions, the target solution(s)/suspension(s) being cointroduced into a particle formation vessel with the anti-solvent, preferably through a coaxial nozzle with an appropriate number of concentric passages.

Other advantages of the SEDS T M process are described in prior art such as WO- 95/01221, for example the ability to process sensitive active substances in a light-free and/or oxygen-free environment.

The anti-solvent used in the SEDST m process is preferably supercritical carbon dioxide, although others (eg, as mentioned in the earlier SEDS T M literature) may be used instead or in addition.

The oligomeric (which includes dimeric) or polymeric material may be any suitable excipient for the active substance, of whatever molecular weight and whether hydrophilic such as a polyethylene glycol, hydroxypropyl methyl cellulose (HPMC) or or hydrophobic such as an ethyl cellulose It may be a biodegradable oligomer or polymer such as a polylactide or glycolide or a polylactide/glycolide. It may be crystalline, semi-crystalline or amorphous. It may be a homo- or co-oligomer/polymer, synthetic or naturally occurring.

Examples, of oligomeric or polymeric materials suitable in particular for coformulation with pharmaceutically active substances, include but are not limited to: a) traditional "natural" source materials, their derivatives and their synthetic analogues, such as acacia, tragacanth, alginates (for instance calcium alginate), alginic acid, starch, agar, carrageenan, xanthan gum, chitosan, gelatin, guar gum, pectin, amylase or lecithin.

b) celluloses and cellulose derivatives, such as alkyl (for instance methyl or ethyl) cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose, microcrystalline cellulose or microfine cellulose.

c) homo- and co-polymers of hydroxy acids such as lactic and glycolic acids.

d) acrylates and their derivatives, such as the "Eudragit"" m polymers, 20 methacrylic acids, or methacrylates such as methyl methacrylate.

e) hydrated silicas, such as bentonite or magnesium aluminium silicate.

S f) vinyl polymers, such as polyvinyl chloride, polyvinyl alcohols, polyvinyl acetates, cross-linked polyvinyl pyrrolidones or carboxy vinyl copolymers.

g) polymeric surfactants, such as polyoxyethylene or polyoxypropylene, or polyalkylene oxides such as polyethylene oxides.

h) phospholipids, such as DMPC (dimyristoyl phosphatidyl choline), DMPG (dimyristoyl phosphatidyl glycerol) or DSPC (distearyl phosphatidyl choline).

carbohydrates, such as lactose, dextrans, cyclodextrins or cyclodextrin derivatives.

Sj) dendrimeric polymers, such as those based on 3,5 hydroxy benzyl alcohol.

k) poly(e-caprolactones), DL-lactide-co-caprolactones and their derivatives.

1) poly(orthoester)s and poly(orthoester)/poly(ethylene glycol) copolymers, including block copolymers, such as are described in US-5,968,543 and US- 5,939,453, also derivatives of such polymers, also such polymers with incorporated esters of short chain a-hydroxy acids or glycolic-co-lactic acid copolymers.

Other suitable oligomers/polymers are listed in the literature on drug delivery systems, for example the report by Brocchini in World Markets Series "Business Briefing", Drug Delivery Supplement The oligomeric or polymeric material is preferably either a cellulosic material such as EC, HPC or HPMC (including cellulose derivatives), a vinyl polymer such as a polyoxyalkylene (eg, polyoxyethylene or polyoxypropylene) polymer or copolymer or a polylactide or glycolide (including lactide/glycolide copolymers). The polymeric material is not a poly vinyl pyrrolidone.

15 more active substances. It may be monomeric or polymeric, organic (including o organometallic) or inorganic, hydrophilic or hydrophobic. It may be a small molecule, for instance a synthetic drug like paracetamol, or a larger molecule such as a (poly)peptide, an enzyme, an antigen or other biological material. It preferably comprises a Spharmaceutically active substance, although many other active substances, whatever their 20 intended function (for instance, herbicides, pesticides, foodstuffs, nutriceuticals, etc.), may be coformulated with oligomers or polymers in accordance with the invention. In particular the active substance may be a material having low aqueous solubility, for which coformulation with an oligomeric or polymeric excipient can increase the aqueous dissolution rate and hence facilitate delivery.

In particular, it has surprisingly been found that SEDSTM may be used to coformulate an active substance with an oligomer or polymer even when their respective hydrophilicities are significantly different. Such pairings might previously have been thought incompatible for coformulation. Examples include coformulations of relatively polar actives such as paracetamol, theophylline or ascorbic acid with hydrophobic polymers such as ethyl cellulose.

For some active substances, SEDSTM enables the preparation of coformulations containing higher amorphous phase active loadings than has previously been possible.

P.OPERUcc68550-O 2ps doc-25/0 DO -8- In a coformulation according to the invention between 90 and 100% or between and 100%, most preferably 100%, of the active substance is present in an amorphous as opposed to crystalline form. The active substance represents at least 10%, more preferably at least 20% or 25% or 30% or 35% or 40% or 50% or 60% or 70% or 80% or 90% of the system. In other words, products according to the invention can contain high loadings of the active substance, of which all or substantially all is present as a single amorphous phase.

Percentage concentrations are weight for weight unless otherwise stated.

In an embodiment of the invention the active substance is selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid.

Where the active substance is indomethacin and the excipient is ethyl cellulose preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 100/, more preferably at least 20% or or 30% or 35%, of the coformulation.

Where the active substance is indomethacin and the excipient is hydroxypropyl methyl cellulose (HPMC), preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 10%, more i: preferably at least 20% or 25% or 30%/ or 35% or 40%, of the coformulation.

2Where the active substance is indomethacin and the excipient is polyvinyl 20 pyrollidone (PVP), preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 20%, more preferably at least or 30% or 40% or 50% or 60%/ or 65% or 70%, of the coformulation.

SWhere the active substance is carbamazepine and the excipient is EC, preferably between 95 and 100% of the carbamazepine is present in an amorphous form, and the S: carbamazepine represents at least 100/, more preferably at least 20% or 25% or 30%, of the coformulation.

*o *e *e Where the active substance is carbamazepine and the excipient is HPMC, preferably between 95 and 100% of the carbamazepine is present in an amorphous form, and the carbamazepine represents at least 10%, more preferably at least 20% or 25% or of the coformulation.

Where the active substance is theophylline and the excipient is EC, preferably between 95 and 100% of the theophylline is present in an amorphous form, and the theophylline represents at least 10%, more preferably at least 20% or 25% or 28% or of the coformulation.

Where the active substance is theophylline and the excipient is HPMC, preferably between 95 and 100% of the theophylline is present in an amorphous form, and the theophylline represents at least 10% of the coformulaiton.

Where the active substance is ascorbic acid and the excipient is EC, preferably between 95 and 100% of the ascorbic acid is present in an amorphous form, and the ascorbic acid represents at least 10% or 15%, of the coformulation.

Where the active substance is ascorbic acid and the excipient is HPMC, preferably between 95 and 100% of the ascorbic acid is present in an amorphous form, and the ascorbic acid represents at least 10%, more preferably at least 20% or 25% or 20 30% or 35% or 40%, of the coformulation.

Where the active substance is a compound of formula S* "\S -(4-chlorophenyl)- 1-( 4 -methanesulfonyl)methylene]-dihydrofuran-2-one) and the excipient is hydroxypropyl cellulose (HPC), preferably between 95 and 100% of the Compound is present in an amorphous form, and the Compound represents at least or 15% or 20% or 21%, of the coformulation.

Where the active substance is a compound of formula and the excipient is a polyoxyalkylene polymer or copolymer, such as a polyoxypropylene-polyoxyethylene copolymer, preferably between 95 and 100% of the Compound is present in an amorphous form, and the Compound represents at least or 15% or 20% or 24%, of the coformulation.

Where the active substance is a compound of formula

(II):

,o 0 .present in an amorphousrm and the Compound (11 reresens at least 10%, preferably at least 15% or 20% or 21C s In certain cases, SEDS-r can allow formation of the amorphous phase of active substances which have (to our knowledge) previously only been prepared in their crystalline phase(s). One example of this is the preparation of paracetamollexcipient coformulations. Another aspect of the present invention provides a coformulation of paracetamol and an oligomeric or polymeric material, in which between and 100% of the paracetamol is present in an amorphous as opposed to crystalline form, and in which the paracetamol represents at least 1% of the coformulation.

Br *e ((Z)-3-[l-(4-bromophenyi)" l-(4-methylsulfonylphenyl)methylene]-dihydrofuran'2"ne) Sand the excpIn such paracetamol coformulationsent is preferably between 95 and 100% of the Compound 00%, more pref erably between 95 and 100%, m preferably 100ound of the paracetamol is pesentleast 10%, preferably at least 15% or 20% or 21%, of the coformulation.

In certain cases, SEDS T M can allow formation of the amorphous phase of active substances which have (to our knowledge) previously only been prepared in their crystalline phase(s). One example of this is the preparation of paracetamol/excipient coformulations. Another aspect of the present invention provides a coformulation of paracetamol and an oligomeric or polymeric material, in which between and 100% of the paracetamol is present in an amorphous as opposed to crystalline form, and in which the paracetamol represents at least 1% of the coformulation.

In such paracetamol coformulations, preferably between 90 and 100%, more preferably between 95 and 100%, most preferably 100%, of the paracetamol is present in P OPERUcc68550-00 spe doc-22/03'02 -11its amorphous form. The paracetamol preferably represents at least more preferably at least most preferably at least 8% or 10% or 25% or 28% or 30% or 35% or 40% or 50% or of the coformulation. The oligomeric or polymeric material is preferably hydrophobic; most preferably it is an ethyl cellulose. The amorphous phase paracetamol is preferably stable, with respect to its crystalline form(s), for at least three months, preferably six months, more preferably nine or twelve or eighteen or twenty four or thirty six months, after its preparation, when stored at between 0 and 10 0 C. It is preferably also stable, for the same period, when stored at 25 0 C, more preferably also at 40 0

C.

Aspects of the invention can also provide methods for preparing the above described 10 coformulations, using a SEDSTM process, as well as the use of a SEDSTM process to prepare the coformulation as described herein. It also provides the use of a SEDSTM process to prepare a coformulation as described herein.

Also provided is a pharmaceutical composition containing a coformulaiton as described herein.

The invention may be applied for preparing a coformulation of an active (preferably a pharmaceutically active) substance and a hydrophobic oligomeric or polymer excipient, using a SEDSTM process, in which the active substance and the excipient are chosen so that the difference between their respective total specific solubility parameters, 6s, is between -5 and preferably between -2 and +2 and more preferably zero or close to zero. The excipient is 20 preferably a cellulose or cellulose derivative such as an ethyl cellulose. The invention thus relates also to the products of such a method, and the use of a SEDSTM process in it.

The invention may be applied for preparing a coformulaiton of an active (preferably pharmaceutically active) substance and an oligomeric or polymeric excipient, using an antisolvent-induced particle formation process (preferably a SEDSTM process), wherein, under the operating conditions used, the active substance is soluble in the chosen "anti-solvent" but the excipient is not. A preferred "anti-solvent" for this method is supercritical carbon dioxide.

The active substance is preferably non-polar, as for instance the drug ketoprofen, and the excipient is preferably hydrophilic, for instance HPMC. Again the invention provides the products of such a method, and the use of a SEDSTM process in it.

The invention may also be applied for preparing a coformulaiton ofindomethacin and polyvinyl pyrrolidone, using an anti-solvent-induced particle formation process, preferably a SEDSTM process. The invention relates also to the products of such a method, and the use of a SEDSTM process in it.

P V'PER'JAc68550-00 -pe doc.22,03!02 12- In some cases, it appears that SEDSTM can yield active/excipient mixes of sufficient intimacy that the initial "burst" of drug release, which tends to occur in the dissolution profiles of conventional systems, can be inhibited or even prevented. Certain coformulations according to the present invention can therefore be used as slow release drug formulations, providing a more uniform rate of drug release without the need for protective coatings or additional reagents. Examples include in particular coformulations of water soluble active substances such as theophylline with relatively hydrophobic excipients such as ethyl cellulose.

This finding is particularly important since the coformulation of an active substance in its amorphous phase would normally be expected to increase its dissolution rate. Previous 10 attempts to inhibit dissolution have instead typically involved placing physical constraints on the active substance, such as by trapping its particles in a two-phase polymer matrix.

Thus, in a further aspect the invention provides a coformulation of an active (preferably a pharmaceutically active) substance and an oligomeric or polymeric excipient as described ,comprising an intimate single-phase mixture of the active substance and the excipient from which the dissolution rate of the active substance in an aqueous medium is no higher for the first 30 minutes, preferably for the first 60 or 90 or 120 minutes, than it is subsequently. Such a coformulation is again preferably prepared by a SEDS T M process.

In the coformulation as described herein the active substance may be a COX-2 selective inhibitor. As used herein "COX-2 selective inhibitor" means an organic compound or pharmaceutically acceptable salt or solvate thereof which is capable of selectively inhibiting the COX-2 enzyme over the COX-1 enzyme.

The COX-2 selective inhibitor may be a diarylheterocycle. As used herein "diarylheterocycle" means an organic compound of the diarylheterocycle genus (or a pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent atoms in a five or sixmembered heterocycle or both of said phenyl rings directly attached to the same carbon atom of a Ci-3 alkylidene linker, said C 1 3 alkylidene linker further attached to one atom in said five or six-membered heterocycle.

15 The COX-2 selective inhibitor may be a diarylfuranone. As used herein S "diarylfuranone" means an organic compound of the diarylfuranone genus (or a pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent carbon atoms in a furanone **moiety or both of said phenyl rings directly attached to the same carbon atom of a C.-3 20 alkylidene linker, said Ci-3 alkylidene linker further attached to one carbon atom in said furanone moiety.

*The COX-2 selective inhibitor may alternatively be a diarylpyrazole. As used herein "diarylpyrazole" means an organic compound of the diarylpyrazole genus (or a S*pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent atoms in a pyrazole moiety or both of said phenyl rings directly attached to the same carbon atom of a C 13 alkylidene linker, said C)- 3 alkylidene linker further attached to one atom in said pyrazole moiety.

The COX-2 selective inhibitor may alternatively be an arylpyridylpyridine. As used herein "arylpyridylpyridine" means an organic compound of the arylpyridylpyridine genus (or a pharmaceutically acceptable salt or solvate thereof), comprising one substituted or unsubstituted phenyl ring and one substituted or unsubstituted pyridyl moiety each directly attached to adjacent atoms in a pyridine ring or both said phenyl ring WO 01/15664 PCTIGBOO/03328 and pyridyl moiety directly attached to the same carbon atom of a C 1 3 alkylidene linker, said C 1 3 alkylidene inker further attached to one atom in said pyridine ring.

The COX-2 selective inhibitor is preferably selected from the group consisting of (Z)-3-[1-(4-broophenyl)-1 -4-methylsulfonylphenyl)methylefel dihydrofzran-2-one, I -4-chlorophenyl)-I -(4-methylsulfonylphenyl)nethyleneI dihydrofiiran-2-one, 4- [5-(4-methylphenyl)-3-(trifluoromethyl)- I H-pyrazol-i -yl]benzenesulfona'nide, 4-[4- (methylsulfonyl)penyl]-3-phenyl-2(5H)-firanone and the compound of Formula (III): 3 C0 2

N

C1 V

N.

3 c N (III) I-(4-bromophcnyl)-l -(4-methylsulfonylpbenyl)methylefe] dihydrofuran- 2-one and -(4-chlorophenyl)-l -{4-methylsulfonylphenyl)methylene] dihydrofiiran- 2-one are COX-2 selective inhibitors useful for the treatment of acute and chronic pain.

is See U.S. 5,807,873 and related applications incorporated by reference herein 4-[5-(4-metbylphenyl)-3-(triuoromethyl)- IH-pyrazol-I -yl]benzenesulfonamide is a COX-2 selective inhibitor approved for the treatment of osteoarthritis and rheumatoid arthritis and is marketed in the U.S. under the tradename CELEBREX4 (celecoxib). See, U.S. 5,466,823 and U.S. 5,563,165, incorporated by reference herein.

4-[4-(methylsulfonyl)phefyl-3-phenyl-2(SH)-furanone is a COX-2 selective inhibitor approved for the treatment of osteoarthritis, treatment of primary dysmenorrhea and management of acute pain and is marketed in the U.S. under the tradenane VIOXJ& (rofecoxib). See U.S. 5,474, 995, incorporated by reference herein.

The compound of Formula is a COX-2 selective inhibitor being developed for the treatment of acute and chronic pain. See WO 99/15503 and related applications incorporated by reference herein.

WO 01/15664 PCT/GB00/03328 These and other COX-2 selective inhibitors falling within the biarylheterocycle genus or more particularly biarylfurananone and biarylpyrazole genera appear to have low aqueous solubility, suggesting suboptimal bioavailability. Their coformulation with oligomeric or polymeric excipients, in accordance with the present invention, can be expected to enhance their bioavailability The present invention will now be described, by way of example only, with reference to the following experiments and the accompanying figures, of which: Figure 1 is a schematic illustration of apparatus usable to carry out methods, and obtain products, according to the invention; Figures 2-5 are SEM (scanning electron microscope) photographs of some of the starting materials and products of Example I below; Figures 6 to 8 show dissolution profiles for three of the systems investigated in Example I; Figures 9 to 19 show plots of crystallinity against drug weight fraction for the systems investigated in Example I; Figures 20 to 24 are DSC (differential scanning calorimetry) traces for, respectively, crystalline indomethacin and a number of coformulations prepared in Example 1, including after 24 months'storage; Figures 25 and 26 are plots of(,d- 8 s against X (see Table 10 below) for some of the systems investigated in Example I; Figures 27 and 28 are SEM photographs of some of the products of Example II; Figures 29 and 30 are plots of crystallinity against drug weight fraction for the products of Example II; and Figure 31 is a plot of crystallinity against drug weight fraction for the products of Example IR.

Examples The following experiments demonstrate the use of a SEDST m process to coformulate various drugs and polymers in accordance with the present invention. The WO 01/15664 PCT/GB00/03328 physicochemical characteristics of the products, in particular the degree (if any) of drug crystallinity, the stability of the amorphous phase and the relative concentrations of the drug and the polymer (ie, the drug "loading"), were tested and where possible manipulated by altering the operating conditions and solvents present.

The drugs were chosen to cover a broad range of polarities, including the highly apolar ketoprofen and, in ascending order of polarity, indomethacin, carbamazepine, paracetamol, theophylline and ascorbic acid. These drugs were coformulated with both hydrophobic (EC) and hydrophilic (HPMC) polymers.

Ketoprofen was on the whole too soluble in supercritical carbon dioxide (the chosen anti-solvent) to produce meaningful results, even under moderate processing conditions. Surprisingly, however, it could be retained to a degree when coformulated with HPMC.

In an additional investigation, PVP was coformulated with the poorly water soluble drug indomethacin.

Further experiments (Examples II and UI) coformulated two cyclo-oxygenase-2 (COX-2) enzyme inhibitors with HPC and, in the case of Example II, a polyoxypropylene-polyoxyethylene block co-polymer, PluronicTM F87.

In Example IV, the drug glibenclamide was coformulated with 75/25 DL-lactideco-caprolactone.

Experimental details The method used was essentially the SEDST m process described in WO- 95/01221. It is envisaged that modifications of SEDST, as described in that document, WO-96/00610, WO-98/36825, WO-99/44733 and/or WO-99/59710, could be used to similar effect.

The apparatus is shown schematically in Figure 1, in which 1 is a particle formation vessel; 2 is a device (eg, a filter) for retaining the particles formed; 3 is an oven and 4 a back pressure regulator; and 5 is a nozzle for co-introducing, into the vessel 1, a supercritical anti-solvent from source 6 and a target solution from source 7. The items labelled 8 are pumps; 9 is a cooler, 10 a heat exchanger and 11 a pulse dampener. A WO 01/15664 PCT/GB00/03328 recycling system 12 allows solvent recovery at 13 (via needle valve 14), whilst returning carbon dioxide to the cooler 9 for re-use.

The nozzles employed at 5 were two-passage coaxial nozzles of the general form depicted in Figure 3 ofWO-95/01221, typical dimensions being as described in that document. Supercritical carbon dioxide was the chosen anti-solvent, introduced into a ml particle formation vessel via the inner nozzle passage. The "target solution", ie, a solution of the drug or polymer, or more typically of both together, was introduced through the outer nozzle passage.

In situ mixing of separate drug and polymer solutions could have been achieved to using a nozzle having three or more coaxial passages, allowing the two solutions to meet at the nozzle outlet.

Selection of a suitable solvent depended on the properties of both drug and polymer, but particularly on the latter because of the potential difficulties of processing polymeric solutions and dispersions. Polymeric dispersions can exhibit very high viscosities, even when dilute, whereas in "good" solvents the polymer matrix will relax and loosen, allowing both a greater degree of interaction and a lower viscosity, important respectively for the production of intimate drug/polymer mixtures and for the processing requirements of SEDST m The analytical techniques employed in the experiments were as follows: Scanning electron microscopy (SEM) Particle size and morphology were investigated using an HitachiTM S-520 scanning electron microscope (Hitachi, Japan). Aluminium stubs containing a small quantity of sample particulate were sputter-coated with a gold layer -300A thick and viewed and photographed under varying magnifications.

Differential scanning calorimetry (DSC) This technique was used to measure sample crystallinity, given that the lower the order of the crystal lattice the less energy required for melting the sample. DSC was used to determine thermal profiles, to monitor the latent heat of fusion (AHf), to identify any phase or polymorphic transitions and desolvation phenomena, and to determine melting points and glass transition temperatures.

WO 01/t15664 PCT/GBOO/03328 A Perkin-ElmerT M DSC 7 (Perkin-Elmer Ltd, UK) was used. 1-5 mg samples were examined in pierced, crimped alumirium pans, under an atmosphere of nitrogen.

The analytical temperature range depended on the drug investigated. Theophylline sublimed just above the melting point, causing difficulties in measuring endotherm peak size. This problem was overcome by adopting a sealed pan method.

Relationships between product crystallinity and weight fraction of drug in the product were also investigated. Crystallinity was derived from the latent heat of fusion (AHf), using the equation: A-l (coformulation) 100 crystallinity X AHf (1000/a crystalline) Weight fraction of drug X-ray diffraction (XRD) This was also used to give aqualitative assessment of crystallinity. Samples is were analysed on a D5000 XRD (Siemens, Germany) between 5 and 300 UV spectrophotometry (Example I) The weight fraction of drug in samples was measured with an Uhrospec T M 4000 spectrophotometer (Pharmacia Biotech, Cambridge, England), from reconstituted solutions of the samples. The absorbance of the polymers was negligible at the wavelengths used.

Dissolution test (Example I) Dissolution testing was carried out using a stirred vessel technique and UV analysis. The apparatus consisted of a I litre round-bottomed vessel maintained at around 37°C in a water bath, stirred by paddle at 60 rpm. The medium was circulated using a peristaltic pump through a 10 nun flow cell. UV readings were taken every seconds using an Ultrospec Tm 4000 spectrophotometer (supra) and analysed for up to between 30 and 60 minutes.

WO 01/15664 PCT/GB00/03328 Three systems were analysed: paracetamoVHPMC, theophylline/EC and indomethacin/HPMC. The conditions for the individual systems were:- Paracetamol/HPMC: 247 nm, 37±0.5 0 C, 500 ml distilled water.

Theophylline/EC: 273 nm, 37±1.0 0 C, 350 ml distilled water.

Indomethacin/HPMC: 235 nm, 37±0.5C, 400 ml pH 7.00±0.02 0.05M NaH 2 P04 aqueous buffer.

A different medium was needed for the indomethacin system due to the drug's poor water solubility. The chosen medium provided a compromise between observing drug release within a practical time span and allowing sufficient discrimination to identify true dispersions.

The release profile characteristics were compared with physical mixes to give an indication of polymer/drug interaction and possible complex formation. The physical mixes were prepared from pre-micronised drug ground (for 1 minute in a pestle and mortar) together with the designated polymer. Samples were transferred to hard gelatine capsules (size 4 clear/clear, weighted by 60:40 tin/lead wire coils) for analysis. The capsules gave no significant absorbance in the analysis region.

Aerosizer-Aerodisperser m particle size analyser (Example II) Particle size analysis was carried out using a time-of-flight analyser (Aerosizerm with Aerodisperser T M TSI Inc, USA). This instrument is capable of sizing dry powder samples over the range 0.2-700 upm. The powder is dispersed in air and the air/particle suspension is expanded through a nozzle into a partial vacuum. The air/particle stream accelerates through a measuring region, where the particles pass through two consecutive laser beams. Smaller particles experience a greater acceleration than larger ones and hence move more rapidly between the two beams. From measurements of the time taken to travel between the beams and the known density of the material, the Aerosizer

T

software calculates the mean size distribution of particles present in the sample. The data obtained complements SEM observations. No sample preparation is required.

HELOS Sympatec m particle size analyser (Examples II and Ill) This instrument uses laser diffraction to determine particle size distributions of solid particulate materials. It is capable of measuring across the particle size range 0.1- 19 WO 01/15664 PCT/GB00/03328 8750 pm. A dry powder sample is introduced, via a vibrating conveyor feeder, into a dry dispersing unit. Here the powder and any agglomerates present are fully dispersed in air.

The dispersion of single particles is then propelled by compressed air and fed through the measuring zone, where the particle stream interacts with a monochromatic high energy beam from a He-Ne laser. The laser light is diffracted and detected by a multicomponent photodetector. The intensity of the diffracted light is then converted into an electrical signal, which is used to calculate the particle size distribution. Again, the data complements SEM observations. No sample preparation is required.

High performance liquid chromatography (HPLC) (Examples U and HI) Compound and (II) loadings were determined by HPLC using UV detection.

An isocratic method was followed, employing a single mobile phase phosphoric acid:acetonitrile (62:38 degassed for 20 minutes before use).

Quantification was by external standardisation. Two stock solutions of Compound with concentrations of 500 pgml-' were prepared in the mobile phase.

Appropriate volumes were alternately taken and diluted with mobile phase to produce a set of standard calibrants in the nominal range 2 to 10 lgml-. Aliquots of prepared sample solutions, diluted if necessary, were then submitted to HPLC analysis, interspersed with the calibrant solutions. Using the following nominal conditions a chromatogram was generated.

Pump: Capable of delivering 1.1 mlmin Sample size: 20 ld (ATI UnicamT M autosampler) Column: 150 x 4.6 mm, ZORBAX T M RX-CS, 5 pm Column temperature: Flow rate: 1.1 mlmin Detector/wavelength: Jasco T UV-975 220 nm Peak response: Area Cycle time: Typically 17 minutes WO 01/IS664 WO 0115664PC17IGB00I03328 All peak arma nmeasurements5 and calculations were performed using Borwiflim chromatography software Version 1.22.01.

ExamplIX The materials used in this series of experiments were as follows; their polarities and solubility parameters are isted in Table I below.

Materia L-ascorbic acid Carbamazepine Indometacin Ketoprofen Paracetamol Theophyllifle

EC

HPMC

PVP

Dichloromethane Chloroform Ethanol Ethanol Methanol -ntiuim dihvdroge Suplier Sigma Chemical Co, St Louis, Missouri,

USA

Sigma Sigma Sigma Sigma Sigma Colorcoil, Dartford, England Shinetsu Chemical Company, Tokyo, Japan Sigma BDII (Merck), Poole, England

BDH

BDH

Rathburn CheinicalS Ltd, Walkerburn, peebleshire, Scotland

BDH

nSigma Grade General laboratory reagent Ditto Ditto Ditto 99.01/1+ Anhyd. 99%/+ 7 cps 3 cps (603) Av. mot. wt. 10,000 AnalaR 99-51/+ AnalaR 99.0-99.4% AnalaR 99.71000/a

HPLC

AnalaR 99.8%+ 99.0+ orthophosphate 0O) (De-ionised water was obtained from a jencons Waterstill 1 400.

Chemial tructr Mater-ia L-ascorbic acid WO 01/15664 WO 0115664PCT16B00103328

CH

2

OH

OH OH Carbamazepine indornethacin O CI Ketoprofen 0 CH 3 I?

COOH

Paracetamol (US acetamiinophen) WO 01115664 WO 0115664PCTI/GBOO/03328 HOa 0 N 'k CH 3

H

Theophylline

H

l"I3CI N N O rN

CH

3 Ethyl cellulose (EC)

CH

2 0 O-0 0C 2

H

L 0C 2 H 5 -n Hydroxypropyl methyl Cellulose (HPMC)

CH

2 0R OR 0 0 OR O -0 0 L- OR

CH

2 0R R is HL CH, or [CH 3 CH(OH)CH1 Polyvinyl Pyrrolidone (PVP) WO 01/15664 WO 0115664PCTGBOOIO3328 Table 1 Polarity and solubility parameters of drugs and polymers studied* *Values obtained from published literature In Table 1, Sd, Sp, and 8b, are the partial solubility parameters representing dispersive, polar and hydrogen bonding effects respectively; 8, is the total solubility parameter, where 8,2 6d_2 8.,2 8h~2 [91; S. is the total specific (ie, polar and hydrogen bonding) solubility parameter.

The principal operating conditions (temperature, pressure, fluid flow rates and nozzle orifice diameter) were manipulated and optimiised. for each drug/polymer system.

Different drug:polyrner concentration ratios were also tested.

WO 01/15664 PCT/GB00/03328 It was found that temperatures in the range 34-50"C and pressures between and 100 bar were preferable for processing these polymers. Anti-solvent:target solution flow rate ratios (into the particle formation vessel) were between 66:1 and 200:1, ie, an anti-solvent flow rate of 20 ml/min was used with target solution flow rates of between 0.1 and 0.3 ml/min.

Nozzle outlet internal diameters were between 100 and 500 m, 100 pm being preferred over those greater than 200 pm.

A 1: 1 mixture of ethanol and dichloromethane (or 1:1 ethanoVchloioform in the case of PVP) was used as the drug/polymer solvent. This yielded dispersions of suitably to low viscosity, enabling processing without significant nozzle blockage. Similarly, ethanol was found to produce low viscosity dispersions for the EC systems. A polymer concentration of 0.5% w/v provided a balance between the ability to pump the solution at a moderate back pressure and an acceptably high material throughput.

To facilitate processing, the polymers used were selected from the lower molecular weight fractions 3 cps HPMC, 7 cps EC and PVP of average molecular weight 10,000.

Results discussion The results of the various experimental runs (im particular yield, morphology and drug loading) are summarised in Tables 2 (ascorbic acid), 3 (carbamazepine), 4 (indomethacin), 6 7 (ketoprofen), 8 (paracetamol) and 9 (theophylline), appended.

The tables also indicate the operating conditions (temperature and pressure within the particle formation vessel, fluid flow rates, target solution concentration and nozzle tip (outlet) diameter) for each run.

The products were in the form of finely dispersed particulates; all were noncohesive, easy-flowing powders with good handling properties. Their morphology was assessed using SEM, which revealed the non-crystalline products typically as fine, agglomerated, roughly spherical particles of the order of 0.05-1 lpn diameter. The homogeneity in the appearance of the particles suggested they comprised molecular-level dispersions. Above the amorphous limits detected, mixtures of such web structures with additional, larger drug crystals were observed in many cases.

WO 01/15664 PCT/GB00/03328 Figures 2 to 5 are SEM photographs of some of the starting materials and products of the experiments. Specifically, Figure 2 shows the indomethacin raw material (at 2000x magnification); Figure 3 shows the amorphous indomethacin/HPMC product of experimental run RASE 21 (2000x magnification); Figure 4 shows the paracetamol raw material (200x magnification) and Figure 5 shows the amorphous paracetamol/HPMC product of experimental run RASF 34 (1000x magnification).

Dissolution tests Figures 6 to 8 show dissolution profiles for three of the systems investigated, namely paracetamol:HPMC (Figure theophyline:EC (Figure 7) and indomethacin:HPMC (Figure The labelling corresponds to that used in Tables 2-9 for the various experimental runs; X is the maximum concentration of the amorphous phase of the drug prior to the detection of crystallinity. In all three systems, there were significant differences in drug release rates between the SEDSm-coformulated products and purely physical mixes of the relevant drug and polymer, suggesting that the products of the present invention had been formed as intimate molecular level dispersions of a drug in a polymer matrix. For instance, the release oftheophylline was significantly inhibited by coformulating it with EC according to the invention, that of paracetamol was also slightly inhibited by coformulation with HPMC, whilst the dissolution rate of indomethacin was increased on coformulation with HPMC (including one sample above the amorphous detected limit).

Degree of crystallinity Plots of drug crystallinity (determined by DSC) against drug weight fraction are shown in Figures 9 to 19. The systems illustrated are ascorbic acid/EC, ascorbic acid/HPMC, carbamazepine/EC, carbamazepineHPMC, indomethacin/EC, indomethacin/HPMC, indomethacin/PVP, paracetamol/EC, paracetamol/HPMC, theophylline/EC and theophylline/HPMC respectively.

Although it depended very much on the drug and polymer involved, in general the proportion of amorphous to crystalline drug present in the SEDS T M products was found to be higher than that achieved using conventional processing techniques such as evaporation and coprecipitation from solvent systems For instance, maximum WO 01/15664 PCT/GB00/03328 amorphous phase concentrations for indomethacin were 25±5% with EC, 35±5% with HPMC and 60±5% with PVP. Up to 10-15% amorphous ascorbic acid was achieved in coformulation with EC, and up to 35-40% with HPMC (Figures 9 and 10). (Note that drug concentration ranges are quoted at the limit of the amorphous/crystalline state boundary, due to the limitations of the method of quantifying crystallinity by DSC and the limited number of data points around the phase change concentration.) These results are of particular significance for poorly water soluble pharmaceuticals, for which the amorphous form is generally preferred because of its superior dissolution rate.

Physical and chemical stability The medium to long term storage stability of several of the Example I products was investigated. In all cases the physical properties of the samples were unchanged even after up to 24 months' storage; the samples remained free flowing and easy to handle.

Chemical stability (in terms of amorphous phase contents) was assessed using DSC. Looking firstly at the indomethacin/PVP system, the drug in its crystalline form exhibits a peak in DSC profiles at 150-165°C, when analysed at a scanning rate of This peak shifts to lower temperature in coformulated indomethacin/PVP systems. Figures 20 and 21 show DSC profiles for, respectively, the crystalline raw material and the indomethacin/PVP system prepared in experimental run RASE 64. The peak at 139"C in Figure 20 indicates the presence of crystalline indomethacin in the sample (which contained 78% w/w indomethacin, with 30% crystallinity).

The indomethacin/PVP samples prepared in experimental runs RASE 70, RASE 69, RASE 62, RASE 66 and RASE 63 (containing 16, 20, 48, 51 and 62% indomethacin respectively), were assessed initially and after both 12 and 24 months' storage in a desiccator at between 2 and 8 C. The DSC results indicated no crystallinity in any of the samples even after 24 months. An example DSC profile for the RASE 63 sample at 24 months is shown in Figure 22; the absence of the 139"C peak indicates an absence of crystalline indomethacin.

Three theophylline/EC systems were also tested, after storage at ambient temperature and without desiccation. The DSC profiles obtained after 24 months for the products of runs RASH 6, LSDA 52 and RASH 14 (containing 9, 17 and 27% 27 WO 01/15664 PCT/GB00/03328 theophylline respectively, in each case 100% amorphous) again lacked definite peaks, indicating no detectable drug crystallinity. An example DSC profile, for the RASH 14 sample, is shown in Figure 23.

In a similar experiment, the stabilities of four of the paracetamol/HPMC products were tested over a 24 month storage period. The storage conditions were as for the theophylline/EC systems. The 24 month DSC profiles for the products of experimental runs RASF 31, RASF 27, RASF 97 and RASF 40 (containing 19, 20, 21 and 29% paracetamol respectively, in each case 100% amorphous) indicated an absence of crystallinity. Figure 24 is an example DSC profile, for the RASF 40 sample.

Thus, coformulations according to the invention, made by a SEDSTM process, appear to possess excellent long term storage stability, with respect both to their physical properties and to re-crystallisation of the active substance.

With regard to the above stability data, it is of note that many of the systems tested were close to the point of inflexion on the graphs of crystallinity versus drug loading. In other words, they were systems containing the maximum possible drug loading before the onset of crystallinity. Other products of the invention, containing lower drug loadings, would if anything be more stable under the same storage conditions.

Solubility effects A relationship was observed, in the systems containing the hydrophobic polymer ethyl cellulose, between the amorphous phase drug concentration and the total specific solubility parameters 5, (S.(6 2 +h 2 see Table 1) of the reagents. Insofar as could be inferred from the systems studied, the trend was towards the maximum concentration of amorphous phase (and thus also the maximum drug:polymer interaction) being achieved when the 6, of the drug and the polymer were equivalent or substantially so.

It appears that drug/polymer dispersion, and intermolecular/interpolymeric chain mixing and interaction, can be maximised by choosing the reagents so that 5P) is zero or close to zero (where 85. and 8.

P represent the total specific (ie, polar and hydrogen bonding) solubility parameters for the drug and polymer respectively). These systems would be expected to contain the maximum amount of amorphous phase drug, lower amorphous phase levels occurring as (56 5 P) attained either a positive or a negative value.

WO 01/15664 PCT/GB00/03328 Table 10 lists calculated values of( 8 .d 5) for the systems studied, together with values of X% (mid-point and range).

Table Drug/Polymer (Sd 6p) Midpoint Range Ascorbic acid/EC 20.7 12.5 10-15 Ascorbic acid/HPMC 16.8 37.5 35-40 Carbamazepine/EC -0.2 25.0 20-30 Carbamazepine/HPMC -4.1 32.5 25-40 Paracetamol/EC 4.8 6.0 1-12 Paracetamol/HPMC 0.9 30.0 25-35 Indomethacin/EC -1.7 23.0 18-28 Indomethacin/HPMC 40.0- 35-45 Theophylline/EC 5.9 25.0 20-30 Theophylline/HPMC 2.0 12.5 5-20 The Table 10 data are plotted in Figures 25 and 26. The maximum amorphous phase contents found for drug/EC systems, with the exception of paracetamol/EC, seem to be in accord with the hypothesis (Figure 25), showing a maximum of approximately 27% amorphous content at 8.P 0. In contrast, for the drug/HPMC system (Figure 26), a minimum is observed at the zero point, with the paracetamol/polymer system again deviating from the trend.

The systems containing paracetamol deviate from the trends exhibited by the other drugs. Polar systems have a greater tendency to exhibit irregular solution behaviour.

Furthermore, if a molecule contains at least two active groups with differing hydrogen bonding abilities, this can lead to anomalous solubility behaviour. Commonly referred to as the "chameleonic effect", this is a combined effect of the solubility parameter and solute-solvent and solvent-solvent hydrogen bonding. Paracetamol is known to form W001115664 WO 01/ 5664PCTGBOO/03328 irregular solutions in Polar solvents [10-12] and contains the functional groups -OH and NH-, which leads to varying behaviour dependent on the solvent environment.

It is of note that attempts to form amorphous paracetamnol using conventional particle formation techniques have proved unsuccessful, this being attributed to the high crystallinity and crystal energy of the drug. However, using SEDSm to coformulate paracetamol with for instance HPMC, a particulate product containing between 25 and of the amorphous drug can be prepared.

io ExaMple U This series of experiments demonstrates the coformulation, using SEDSTm, of a cyclo-oxcygenase- 2 (COX-2) inhibitor of the formula

ZS

0 0 0 Cl ((Z)-3-[1l44-chlorophenyl)-1 (4meanesulfonyl)methylefe]-dihydrofuran 2 -ne) with.

hydroxypropyl cellulose (HPC): Structural Formubc-

H

2

RR

JOR

OR

0 0- OR COR Where R is H or [CH.-CH(CH 3

)M-H

WO 01115664 PCT/GB00/03328 and: "Poloxamer 237" (P-237), also known as PluronicT F87, which is a polyoxypropylene-polyoxyethylene block copolymer of the chemical formula

HO(C

2 zHO)40 (C 3 HO)37(C240O)6HI.

The reagents used in the experiments were analytical or HPLC grade.

For the solvent used was a mixture of DCM and ethanol which could dissolve both the drug and the polymer together. The (HPC drug) concentration was varied between 0.5 and 4.5% w/v and the DCM:ethanol ratio was altered where appropriate to increase solution saturation. The ethanol helped to lower the viscosity of the HPCdispersion.

The operating conditions for were 90 bar and between 50 and 70C. Higher temperatures facilitated solvent extraction. CO 2 flows of up to 20 ml/min were used, with target solution flows of as low as 0.1 ml/min. The conditions for each experimental run are summarised in Tables 11 and 12, appended.

For the operating temperature was 35"C (due to the relatively low melting point of the polymer) and the pressure was varied between 75 and 100 bar. DCM was used as a solvent for both Compound and the polymer together, with solution concentrations between 1 and 3% w/v. The CO2 anti-solvent flowed at 18 ml/min and the target solution at between 0.1 and 0.2 ml/min. Table 13 (appended) summarises the operating conditions for each run.

In both sets of experiments, nozzle outlet diameters of 100, 200, 400 and 750 pm were employed, and either a 50 ml or in some cases a 500 ml particle formation vessel.

Results discussion Compound and HPC The results are given in Tables 11 and 12, appended. The best yields and particle sizes were obtained in run 14, using 85% w/w of Compound this gave a 95% yield of free flowing rounded/plate-like particles with an average diameter of 3.8 pm (Figure 27, SEM taken at 4000x magnification). At 30% w/w HPC (run 17), a 96% yield was obtained but the particles were more flake-like and agglomerated, their average size being 13.1 pm. HPC concentrations of 50 and 80% w/w gave large (20.7 pm) coral-like WO 01/15664 PCT/GBOO/03328 agglomerates (runs 21 (Figure 28, SEM taken at 2000x magnification) and 22). In all runs the recovery of Compound was greater than Generally, nozzle blockages were reduced at lower concentrations (eg, about w/w or lower) of Compound For some runs, a 50 ml vessel soon clogged with precipitated solids; a 500 ml vessel was substituted to eradicate this problem.

Particle agglomeration (and hence large particle sizes) could generally be reduced by decreasing the process throughput, for instance by reducing the concentration and/or flow rate of the drug/polymer solution (whilst still maintaining a near saturated solution).

Results discussion Compound and P-237 The results are given in Table 13, appended. The smallest particles of pure Compound were produced in run 38, using a 2% w/v target solution with a flow rate of 0.15 mil/min. These conditions were used to produce coformulations for dissolution testing, as well as a control batch of pure Compound The recovery of Compound in all samples was 100%.

Degree of cryslalfinity Products were subjected to DSC analysis to determine the degree of crystallinity in the Compound present. The results, as a function of drug concentration, are shown in Tables 14 and 15 below, for the HPC and P-237 systems respectively, and are illustrated graphically in Figures 29 and 30 respectively.

Table 14 Crystallinity levels in HPC systems Concentration of Compound A- coformulao Crvstallinitv w/w) (by HPLC) Jg Unprocessed Compound 96.1 100 100 94.2 98.1 100 94.0 97.8 100 94.2 98.0 WO 01/15664 WO 0115664PcTIGBOO/03328 Table 15 Crystallinimvlevels in P-237 ystems Concentration of Compoundffm (0/ow/w)IbHf~ Unprocessed Compound

(I)

100 AHg coformulation Crystallinit 7960o 100 93.6 97.4 64.9 79.4 66.4 81.4 48.1 70.3 46.6 68.7 20.8 40.3 0 05.-0 The results for both systems indicate tha crystallinity is significantly reduced as polymer content increases. The ireduction is nearly linear for the P-237 system, but for to HPC a polymer content of at least 20% w/w is needed before crystallinity levels start to decrease. For both systems, a 100%/ amorphous product was achieved at druag loadings of 20%/ w/w or less.

WO 01/15664 PCT/GBO0/03328 Physical and chemical stability A representative sample containing 20% w/w Compound and 80% w/w P-237, produced using a SEDST m process as described above, was stored for 13 months in a screw-top glass jar, under ambient conditions (10-27*C) and in the dark. At the end of this storage period the sample was found to have retained its initial physical properties, ie, it was still a free-flowing, easily handled powder containing discrete particles. It had also retained its 100% amorphous nature (assessed using DSC).

This series of experiments demonstrates the coformulation, using SEDS T m of a COX-2 inhibitor of the formula (II):

'O

/S

0 0 Br ((Z)-3-[1-(4-bromophenyl)- 4 -methylsulfonylphenyl)methylene]-dihydrofuran-2-one) with HPC.

Apparatus similar to that used in Examples I and II, but scaled up 10 fold, was used to carry out SEDST m particle formation. Both Compound (II) and HPC (as used in Example II) were dissolved in acetone, at an optimum concentration of 2.0% w/v. The preferred operating temperature was 60*C and the pressure 120 bar. The optimum target solution flow rate was 1.0 ml/min, that for the supercritical carbon dioxide anti-solvent 200 ml/min. Products containing 10%, 20%, 30%, 50% and 70% w/w Compound

(II)

WO 01/15664 PCT/GB00/03328 were prepared using these conditions, the exact conditions for each run being summaised in appended Table 16.

For some runs, as indicated in the table, a lower molecular weight (80,000) grade of HPC was used.

Experiments were also carried out using DCM:ethanol (35:65 v/v) as the solvent, a solution concentration of 1.0% v/v, an operating temperature and pressure of 50'C and bar respectively, a target solution flow rate of 1.0 ml/min and a supercritical carbon dioxide flow rate of 200 ml/min. The operating conditions for each run are summarised in Table 17, appended; a product containing 90% w/w Compound (II) was successfully prepared.

Results discussion The results are given in the appended Tables 16 and 17. Sample crystallinity was assessed in each case by DSC; the results are shown in Table 18 below and represented graphically in Figure 31 (plot of crystallinity against drug loading).

Table 18 Compound f Latent heat of fusion Crystallinitv Run N' Cone. W/W) Coformulation Starting material 74.84 100

N/A

5.6 29.6 17 6.2 33.3 17 10 44.4 18 64.7 96.1 19 31.6 84.5 48.9 93.3 23 58.6 92.2 9 63.3 94 24 0 0 0 0 0 0 13 WO 01/15664 PCT/GB00/03328 Thus, the products containing 20% w/w Compound (II) or less (run numbers 13 and 25) had 0% crystallinity. After storage for approximately three months in screw top glass bottles, at ambient temperature (10-27°C) and in the dark, these samples were found to have retained their 100%/o amorphous nature. They were also still free-flowing, easily handled powders, as initially.

Example IV This series of experiments demonstrates the coformulation, using SEDS T M of glibenclamide {4[2-(5-chloro-2-methoxybenzamido)ethyl]benzenesulphonyl}-3cyclohexylurea, an anti-diabetic drug) and 75/25 DL-lactide-co-caprolactone (Birmingham Polymers, England).

Supercritical nitrogen was used as the anti-solvent, since supercritical carbon dioxide would plasticise the amorphous polymer excipient. The glibenclamide was dissolved in methylene chloride. The anti-solvent flow rates were between 15 and litres min', those for the drug solution between 0.05 and 0.1 ml mind. A 500 ml particle formation vessel was used, at an operating temperature of between 35 and 60°C and a pressure of 100 bar.

Results discussion Coformulations having drug:polymer ratios of between 1:1 and 9:1 were successfully produced under the above conditions. XRD analysis confirmed that although the glibenclamide raw material was crystalline, all of the SEDSTM products contained 100%/ amorphous phase drug.

For all of the coformulations, residual solvent levels (measured using headspace gas chromatography (Varian T m were below 300 ppm, surprisingly low in view of the poor mass transfer properties of supercritical nitrogen relative to supercritical carbon dioxide.

WO 01115464 FCTGBOOIO3328 There now follow Tables 2-9 (Example 11 -13 (Example HI) and 16 and 17 (Example III), referred to above.

Ascorbic Acid Result Table 2 Drug N- Drugtc in Cco" C.Flow Raw. C02 nb. Terrip Ntse d,itucn Yicii DSC P.A. Peodi. bry R-Asri 0.2 EC 10Opi 0 Etl'hu. 20 34 120 100 It fPet panteOvl H40 210 so0I ie pancolil. Large trid.

RASFIO 01 3 C I ory, 0 '0 Eiki_., 0)3 20 34 t0 100 s0 blocks ND I0S.4 C02 purri pobkoe lirw 11i 1 01 EC li:ps 10 :0 E01001 0 i 20 134 30 100 1NO I P.I.,olt WNf 176 1 71 L %S Fit 04 EC l0cp, 0 ;0 Eh,-oI 02; 20 24 toI 00o 6 Fine panscola ND 123.7 57.1 RLASMS 00 EC I Ocps 060 Ediaool 03 0 14 to 00o 71 FIne garci,uiii SD0 2 ILASF96 (SW) 0.1 EC 7cps 000 Methaonol 02 20 34 to 100 62 riot bite pat~onlau ND 2.72 2 1ASi (S W) 0l EC 7ops 010 I &Iehaial 02 20 24 so 100 40 Pnte white partcule NO 29241 17 2 RAkS')! [SWI 02 EC Uops 05!0 16tihIda 02 20 114 00 100 29 fic white paricuolate ND $1.29 21.1 R.ASF99 1SW1 02 EC 7cp 0 :0 %ilunol. 02 20 34 t0 100 40 Fie white pzniculjic NO 64 393 Ethanol /DCM LSDOIR 02 14PIC .s 010 1) 02 20 34 so 100 61 Fine -tw powdv, Atucotoes Norte 24 Eitanol I 0CM LSOA19 0. HS I-Ip5r2 05!0 11.111 3 20 24 30 100 7l fiie -hirepowdier AOt0f96 48 LSORA2O 1.0 H4C .cps 250 E 11W:I1 03 20 3A to 100 SI _Fineeslipouder Areatete 123 69 Ethanol I 0C.M LSD 1 1S II'C jcPs 0 50 11.11 02 20 24 s0 too 41 Fit. f..htiePowder Asi'eeni tI r5 nO..ei 182 74 15042 1 40 5 C 10ePS 0.20 Etha 03 20z 34 s0 too Is Fine off-whtite po-dec NO 226 36 LS".2 4 1 EC 10cp3 050 Ethanol 01 20 34 s0 300 93 Fine off white Powder 14D 221 91 LSDA3 4 1 EC 10cps 020 Cilcoo 011 20 34 t0 5on 64 risng off-white powdrf ND 222 1 91 LSDA24 2.0 EC l0ops 0 20 Ethial L) 20 34 30 100 63 Fine olff-hiie powder ND 222 71 LSODA.9 0 1 EC l10p 0.50 Ethanold 02 20 24 g0 100 11 fine obite power ND 24 lB IMfitO 0 CC 1tp 00 Ethisnit 03 20 34 50 too 06 Fine -bite po-ilet Hurt NIe AllI csp.t.e,te -dot a too carouoens mule NAN.apenl.N.N.dtnmo bJ.At-Not3ppJk3ble. NO.Noidetermirsed Carbamazepinc Results Table 3 [E pnn- n Dn~1 Cons Cone 20 NWA 0 ELI-end imoiin 1.1 ln.m.n n-0,2 ,st, 2 20no d..wme Yield lAto 61 Pi,Ci Oeneioomse Fi., nebsie po, Size bni h SEMI

NO

NO

ocp .iPiodi~ Dg PMolooin SEM) (All.1tp) UV (wI.i Acicusarionitti mm Aeco.tzots 0yi 41 &i ozz~o~iei~eO .j 19 4 Do Fizz .ohie psinedon LS1240 U 5 IMC 0 5 (1:11 02 20 100 p-d.

LSD&S 1 NPMC 05 (III) 02 to0 20 50 w0 $11 sessscp.e D cct Ethsool. DCM AcimiuvniLllii SD %9 02(PC 0 1.1s 0.2 0 0 50 oo0 48 Fine .4,iso pnmidw Dseooin 2 42 Esisosol I DCI 1004 10 1.0 1IPMc 01 0Al) 02 Int 20 50 500 15_ F."e wise powdt NO Acienlar 79 64 EsLsWcd /DCM -Agzpflowit so-ei LSDAL I 0161 lIPMC 0.1 9 0 20 $0 500 45 hin b-ic p-doe 05.0.0 eeoo Noms Ehzipol 0CM 2 LSOA12 1.5 IPS-IC 05 l:lt 02 s0 20 10 500 951 Fine -hspowdn ND AcicuIw 57 07 LS1A613 00 ECle s 05 iiisi (III 02 o 20 50 000 B0 Fn gsi oen ND Acsniml. 26 43 Ediwil I DCM ISDA1 0l 020 EC Ups 01 (1 1) 02 01 20 s0 500 so Fine h.,n P..&on WD Aciensi. Is 29 Ussmiol I DCM LS0415 10 EC 7ps 05 (1:11 02 30 20 so Soo 94 Froe hIic podie ND Aciesuv 51 Eihwiol I DCMs LSD0k16 0 167 ECln 03 (1.11 0.2 so 20 so 500 70 Floe biw pewdc ND Acimu None Edussot I DCM -9-0 Ac"nl~ ih ~i LA1713 5 01 C 7cv,~ 05 1 1) 02 to 20 s0 000 99 Fine wI- iieodcr ND lND~ir NoS 24 LSD06l0 116 EC ?cps 0.2 :1Ii 02 to 20 so 5o0 94 Fine hiss poodie ND ND None 7 Esisezl I DCMs LSDA 0156 EC lps 005 (1 1) 0.2 0 20 50 So0 94 Time -ic pod WD ND, 61 Eh-ool I0C LSD64 0 211 ElM 0.5 (1:11 01 t0 20 10 200 02 rimn.e nI-isindni. NO ND 13w NA-Not spplicobl. ND NSmdctzniizd A rwn-cznnpontil nozLe was used sn ill experismns Irndomethacifl R :uiS Tiblc 4 Ds S.A CA. VAo 1o, 0 6 orq P*C- It- T-0 ,~~5oDI P.20 ong SOi. 0 20d 0 V 0 ,2 A .oo2~. Is 2~5 S 21 I 402 liwoll HI'mc E00,0n6f ios,.a: timlIC WA I2 DC2.lI 11 2 20 073 DcSI 22 @2 2 I 12 lao 2 is 72 Eo2..2I .04 A *o No N L.D(M 2 05 llAI all 22M(11.026 g RISCIP DC7.I~i2 .loL J .L 62 2 00 10 62 h.fr.A h~ s~ P6 N7 2 .o1% IS N2 £AIOc t,

W

@AO2' DCM2II I2 @2 -W~os 910.. as.2 I 0 r 0 2 9 2'iC T.04. EAES c5s2 01 .J5 Clf 00222 a2 I 0 t 7 62- 22 Is Whi 0044 2.00.20AA. 2 021200oi2F.- IPi 22~ EAEl OCsI22 ooD@ C.I2 22 02 1023S24 2 ,.l.00 o,,o 20 2 1i0.006 IIM E Io sI a I EASIOI D'12222 @47 go dc522 5 0 2 00 7 270.1 sWs 20 s, o E2., MtI 22224 @AE (422 60 2.s 2 05222 0S2 6 22 2 14iT2. 0 A. 000 2 1ILASM 06 DP52 I II al 1-41 01 EAES g-2i 22 F 02 n o (622 02 2 7 6 50 2 2oo2.220 ,,20 020 .00 n 1.o hk [1 06' 111O 1 t s B l'W 221 0.50120 EA I0*l2I jj 2 2 5 0 04 i. 2.o0.is@ A.i4 6,5i o2 00 2 (*00,42 OcrI m,.4 I22640 I ll%11 6' M oZ9it -LASE,% Dc-4I 220 j117 02 0(522 I 20 I7 I~ 24 In !a i i0 02e02 Aw W200, .07j 000 a E.4 DCAiI a IS 2 02 075 I1 1 02 210 in 60 224 21 240,200220 is.A Ii, 20 It (iil OCil II 101 @2 05 02 204 022 to son 24 knwvho220 o-.m6os M06 002 .0A20 72 A t-o -2 -ko. 0 W dl 0700-4*p t.NO4. Lndomethucsf Rsuii ribic

A.

H

pf..j.p DSCf 4'6 a' ON 801 28 11 to5 [on x .4 4 O SO .4 40. 4 8s5(5 555 Ats PI44 C, o~ ISO .4 s s o 3 s b 4408 444440 .No 1 5,o 4 I 54.)I 04 IS ko4 E. IPs 4S xsoA 018~ so- 4: v.'tc~ 1 4 C4.ob, 2 58 7 3 4 2 451 d44 4 55 44P.444 545. 4-9444 5 444044 5IIE IflL..n .w W4L, M Itk 4. 4g(8..44 0 5 55 0 0 i It I a] 84 I 554.( o o IN i 8*0089 '24,r5. S 5545 5 44044 02 2 8 3 4 8 5,,8J844 4 .4 4 1a45 pv5 5555444 a 5 51 41 70 'aa A IStS fl4..s54, 10 30ss~ 85 11..,44 05 F- so, to, I ,is 24 ,2 03 55~04444* h 48bu kV 5 vp 4I -a4404 L- 54.4 44,54 488 544544b44F" 84500 fl444o.44 5 PVS4054 5 flrs~r. 45 78 5 48 54 75 PP44 ±Li± 48 55~c 14144r44 Is 17 0 6 j,1.2Z4.S. 6 IS4C7 54h F0458 5 0405 j 5 3 4 10. 444 4444 54 a Z -A LA- 4445(0440 ub4 I I IDan 137 5 5 0 s( a 8 4 C o 5 Fsb..4C.8 5 5 5 411 F1, I* 4 o 40 W0 4- 48 155 1 1..0 44 150444 lc 857 EC 4" 0 85 8 Do,4CM. 05 58 45 so 444 11 No s 4445(h..A4 "C1 a i 0 1 U~SS 04o.4 4 C'55 85 Us4'4 85 50 54 38 44 5 Y4.oo4~ 00 40 2 4 ro USO~~sAI .4544 451 4 8..0 8 8 5 5S 8 4 445.d5050 0 1245 1~4 854 SC., 8 04o4 @5 455I0 4 58 0 40

N.

120545 i E4.. In Sam525, fl .40 j 8 5 45 Mn 4 4 L5854. (4'osj 88" IC IDP 31(545 8 5 8 54 F .0 o 5~ 4 4 4 L50555 &A-o4 I 8 s, 88 C 05 I 4 is0 44 4 *5 4 O4 09 0

C.,

449 -'4 A0 ts) Ketoprofen Result Table 6 Drug Conc.

Pelymer Conc'n Solution Flow Rate C02 nlow Presure Nozzle tip dimeter (iuml rouc' DecP7i Size Morphology lm.by SEI) (by SENI) Exprimfent I..-,ev/vi I ronr Iw v Fine~ w: A RASCI 1OS ltPMC 3cpi 05 11n 0, 1 2 37- 0 100 147 4 ntcula I <01n I A D i cC- ILW 11 Ethanol /0DCM SO I 41. particulate DA0 Ar morphous 3t ren ate ~rphns5 morphous anore ate Drug in OSC Peaks Product by (AH .1/1 UV (Wtl %1 Noone 01 39 None I I t_ 3c s If~ 1) 507s I I Ethanol D NJ I Fine hit n.ASGi 05 nr.Mt cps U.!L 0il U.1 i I Ethanol 0CM Fine white Amorphous LA S G 4 0.5 HPIC 3eps 05 (1 1) 02 20 137 So 1 2 00 45 polaital -02x0.2 asneretate None Ethanol /10CM Fine white Amnorphous 03 HP.NC 3cps 0.5 (1:11 01I 12 37 80 200 32 pariiculate 021 n02 anselteatr None 6 Ethanol /0DCM Fire white Amorphous RASG6 a S HPS.C lcpi 0 5 (1 11 01t 20 17 100 200 42 1parculate 0.1 no I 11aCrenate None 4 Ethanol 0CM Fine white Amorphous IRASG7 05 HPC cpsj 05 01 20 37 80 500 383 panicolate' 0 2%0 2 aegregnte None I RASGS 5 NA 0 Ethnnol 02 15 5o 100 200 0 No product NA NA NA NA- RASG9 5 NA 0 0CM 02 15 371 30 200 a No product NA NA NA NA RASGIO S NA 0 Acetone 02 15 37 80 200 0 No product NA NA NA NA IEthanol f DCM Fine white Amorphous RA Sr, I 1 0 5 IIP\C 3cps 0 5 (1 1) 0.2 20 So 80 200 39 particulate 0 3 x 0.3 1 aggrelgate None Ethanol f10CM Fine whtite Amoruphous RASGI2 0S HPSIC 3cps 05 (It1) 01 20 50 so [00 47 ariulate O0.1 su.stnrenate None 12 05 Ethanol/ 0C2.l Fine white Amorphous 7 .SG I 0.5- HPNIC kcps (I C I 02 20 S n SI) 10 45 Particulate 03nO) 3 Jereqate None 22 All experiments used a two component nozzle NA Not 2pplic3big. ND Not deurmined Ketoprofen Result Table 7 Drug Cone.

P01) mcr Concen SolutIion Flow Rate Nozzle tip diameter yield Product Size Morphology tby SEMI Dru 0Iin Product by UV (Wt 11. C2flow I Im Presure DSC Peaks (AH 1/51 Ethanol Ccp 05 (I 01 0 50 0 200 0 No product NA NA NA NA RASGI3 05 EC lcps 05 (I I) 0.1 20 37 so 200 10 White cobs ND ND ND NA E~inoI 0CA Fine white LSDA:2 05 1 HPNC 0.5 Eta(1: 1 01 20 50 so 100 31 pmisder NA Atirtees; None 1 22 05 Ethanol /DC.M Fine %sh,ie LSlA23 0 167 HP'MC (1 (l1 01 1211 so 1 o 200 45 1po,%der NA Aavretl3tes None 7 05 Ethanol I DCM Fine white LSDA24 0.25 HPNIC 0 (5 1I) 0.1 20 So g0 200 39 pow~der NA Avereevsles None 11 05 Eihanol I 0CM Fine white LSDA23 1 0 HPMIC 0 (1 1) 01I 20 So S0 200 7 powder NA Asitreeati:s None Ethanoll /0CM LS0AM IS5 IIPIC 0S (1 1) 01 20 so so 2D0 0 ND ND Agitetactes I ND Ethanol 0CM LSDA27 4's HPM11C 0S 01 20 50 s0o 0 0 No Prwliici NA HA N4A NA Ethanool I 0CM LS DA2S' 4 5 IIPMIC 0.5 (lU1 0 1 20 s0 s0 200 0 No product NA NA NA NA Ethanol; D CM. Fine whire LSDA29 4.5 I-P.IC 015 (1I1) 01 20 50 80 200 3 Powder ND ND None 49 Eihunol I 0CM% Fine %hite 453 HPMIC 03 (1.11 01 20 S0 t0 200 2 Pit der NI) ND None 52 Etinal I 0CN Fine whitc, LSDA36 4 5 HI'MC 05 01. 1 005 ION is 80 200 1 po'sder ND ND 83 84 Ethanol I 0CM LSA9 225 HPMC 0.25 0 052 20N S0 80T 0 W.rd NAN A N All experiments used a wo component nozzle NA. No::ppliczble, ND Not determnined N -In these twoeipeririLsnunitrogen was substituted for C02 louzrcin Umin measured atambient condiions)I Parocetamol Result Taible 8 Drug__ -pci)nn Soinn" Nozzle up Dmg in C-com. n-o. Itse C02 flo. Ten.p P-c. diarwena Yield moeloO p SC Peaks Ptodoct by Eneoc. iioln3 Sol ni Pois-e (%.4n1 Polnne Soleern Imlmienr (menliin) (*CI (bar) lpnn 11.1 cnonrs SEI (M-11110 (IV (Wt% Edmono I 0CNM Eha.d'I DC% Opm dianene, R n.9F77 0 17 W"-I MPUC Rol 030 0:I1) 01 20 so 120 So0 69 Fine po..len i.!I.hda.ak N~one Ethao, 0CI 14PC Ethaol I DCM Whoicea ra R.ASFI0 0 17 (1 Sp 0 i0 (III 01 20 so 120 how' 31 Fist poasle dolusua Nomo 4 RP I 0173 11:11 010 III ID 0.1 20 127 10 nom, 63 F."opoodc" OSSOOLI None 1 19 1 010 ~tmIf t2C\% EthanolI DCM Fiat paed"le peodued -1oilIoopm ae""o A (.S3 1:11 IlItI3 0.10 21I 0 0 27 to 500 60 sorm hand Iaops 80ve 0 NO Ethnool. 'DCM Ethsanol; CM PiOarilt adate* as .noOuld RASF34 0 M (1 Il NPI'C c l op s 0. 1 11 01 215 37 t0 sin ND "aoEspes None ND Ethaol I 0C.I EuthmooI 10CM ommg~~d55 RASFiS 017 1) WP\IC sp 0.50 (1LJ1).. 0.1C 20 10 120 200 17 Fone oo-dsc dchm0 None 17 En Oal I Ethaoin I 0CM 0. ASPI (017 (11) NPO.ic 1e 010 11. 01 o1 so 120 000 62 Fine pode 200nm spheres None 29 Edoecs/ DCM EthemoI i 0C.N Fico po-do. hlar. pncss., RASM4 017 (1:11 HIPMC Cops 0150 12L... 01 20 so I'0 200 60 pic~ie.0o.5I like ph.a a 17 Eroial I OC.\l RASF96 I0RS) 01 I 1 1 C 7 cps 010O Methlanol 0, 00 3d t0 00o 65 Fin ponder NO 65 48 1 Ethano I DCm R ASF97 IRSI 0 17 (1:11 EC 7.n 050 haniiol 00 00 24 t0 100 66 Fine, poder NO None 21 Ethanol OCM, Eslool I D(1.

RASF98 IRS) 021 (1 1) HP.%C leps 000 [1:11 02 20 34 to 0oo 41 FAw poder NO 02 28i EIdonoli 2C.M E Ihoeo 02 2032CMto 74 R.ASV99 1RS 1 100 01:11 lfC o 020 E 1 1) 02 20iot 00 7 Ppoed NO) 10) 7 lL'.SF 1O3 1 C I EthoI IDCMl OCNM 0 I, IRS 20 HP'.IC 3g. 00 0 02:1 00t4 o 100 76 ine poode NO M211 82 RASF 104 -dua"/C EdsaolI DCM IRS) 0211" (1:11 EC Ups 050 111 02 00 34 to lor) NO Fine po-dff ND 1 8I 34 RASF 103 Ethaool/ DCM Eslson..IDCM (0.5 00 It11 EC cps 050 1. 0 z 20 34 00 50 10 Fine pdcr ND 164 12 LSOA3S 0026 EthmoI EC10cs 01 Ethsinol 0 1 70 37 100 2on 46 ?in. him pode NOD 1 0 Ethanol DiC~. Ed~oonl I OCM LSDA;7 0006 (II) P\IC- 0 1 1) 0 1 00 10 1201 200 44 64.poed NO None I Eshsoo DCM Ethanolf I D.1 LSDA47 0066 11:11 HPMC 0A1 (I'll 01 20 M0 120 000 64 Fine 0,.epodev NI) None 2 ILS11711J41 0079 EM-ool EC 10cpi 0 5 Eihl~sl 0 I 70 37 100 ?00 9 Fine hire owd ND 1 1 LO II 079 Ethanol EC 7 -pa 0 1 Esonne 0 1 0 0 37 100 100 16 Pone 0lim powde 1D Noset I All qonpenims cld 0 con epoeeol ale N-,c p~c6I DNcdnrio NA--NcI3fpIkabIc. ND-NIcIelvinnnincd WO 01/15664 PCTGBOOIO3328 3 I ~it i~ in

II

Ia 3- .0 .4 3 2 0 F F I I I itii~ Ii ii ii I iI~

F'

u U 1

U

S F F F U, ,J e'.

0 0 3 3 2 0. C~ o

V

S

2 2 2 2 2 0 0 I 1: 1 0 0 0 0 I

U

o 0. 0. 0. 0.

I I I I I I: 0

U

002

I

liii 2 0 0 3 0 0 0 0 Ii ii'' ii U

II-

3 2 9 1 2 2 2 2 0 0 0 0

'I

0 0 0 0 7 7 5-, 0 0 0 0 0 0 0 0 z It ii

OF

I

a C Z i'i~ iii.

S 3 3 U S I I 21 21 21 01 01 0 I DZI 21 121 OZI 91 az

F

1 2 2

*J

z g lab

U

3

I

0 Run 2 3 4 7 9 I I 12 13 14 16 17 Sol-rit 1:1 v/v D)CM/EtOHH DCNL'EOHl I v/v 1:1 v/v DCNIEtOhI IV/v DCNI'EtOH CnAVEtO! DCNI'EtOlI 35:65 v/v DC,\EtO1I 35:65 v/v DCNWEtOII1 35:65 v/v DCUEIOI I 3 5:6 5 v/v Table I I Compound and H-Q 152h. I-a Soin. I Nu zze q E Porticle Cent, (%rul Flow jEo (W (bar) L W Saz 4.5 89:11 18.0 0.2 90 65 300 0.1 73 16.2 (A) 4.5 119:11 19.0 0.2 90 52 300 0.1 72 3.3 (A) 3.5 116:14 18.0 0.2 90 60 280 0.1_ 70 7.2 (A) (16.7) 3. 26:14 18.0 0.2 90 70 250 0.2 69 19. 7(A) 0:100 18.0 0.2 90 70 30 0.2 4 3.0 100:0 18.0 0.2 90 70 300 02 47- 2.8 0 54t350 18.0 0.2 90 70 IS 0.2. 24 07 30:70 18.0 0.2 90 70 10 0.2 40 0 7(6.7) 1.0 50:50 18.0 02 90 70 10 0.2 53 1.0 1M0.0 E 20. 0 0.2 90 67 120 0.2 72 26 1.0 85:15 20.0 0.2 90 70 110 02 72 22.1 1.0 85:13 20.0 1 0.1 90 70 20 021 73 3 03.5 89:11 20.0 1 0.2 90 7 I S 02 97 1.0 5: 20.0 0.1 910 70 150 02 95 3.2 (79.0) I 1.0 7n:30 20.0 0.2 90 70 43 0.2 84 17.7 1.0 100:0 200 0.1 90 70 IS0 0.2 95 1.0 03) 20.0 0.1 o 70 6 02 96 1.

Commnent Morholoffy I DescIItIoli C1lets otrounded particle Small nozzle tip causing large 2umn rcssurr build up clusters of rounded particle$ New 0.1mmtip. Blockagrs agpn 2uin and needles S5uma CUfl prcig problems.

cluera of rounded particles Large presurm build up 2um. Some needles.

Clusters of r uofowhunrdued particles Lagrnozetiizs o ec Ag~uinst~ rumde/plte ike Hig oncsntim oionn(~ s.

particls At2u Usrougltnto ig yiel Clusters of roundedpatclies Drugonlyat o. run 12U7U, Urn conditions.

Aloageaics orlat e likece Reduced nozzle blocages with higher pm.amce <ml 2nele -pme cotet.

Ag~lmaacd rundd patices Pr rnzaug apes atob e e s ar <2clm.rte No agiomatet motreoagoradisouin ClsesAgg omrate p o flke ailes P Rtlep ea smllr tn In w S a rtilesu<a sml nedles Reduced oli lowz Table 12 Colvir(3nd IE nd "1PC- Fln olvent Ltn f~Q n.-01 Nox I tsi kd b~S MoboooLnsI CommeriM Cousc, Flow fI) (u )Se C'5 m MrblEV eIDO IIv 10 50:50n 200 0. 0 0 C 0 ran ooiA m id run ceavig w d 8 35-65 v.'v .0 5 0 200 01 9 70 2 0.2 73 mtra D)C,\'EIOI Agglomate4'Rised Platelike soivetmdilio Ohdtvc 19 2 1.0 (43.6) 20.0 0.1 90 70 40 0.2 89 29.4 partic maximum stur tOIL 20 L~ol 10 0.3.69)7 0 Agulomffaedt'Ised plate like Drug oion rnshcd calmad rn.

2 0 :1 0 V 9 0 30 .p a r t i c l e s R u n b a n d o nl e 22 5CNIttol 1.0 (50:70 20.0 0.1 90 70 45 0.2 74 20.7 particles frompluging tenozzle reio.

22 20C 90 iO1H 20:80 20.0 0.1 90 70 12 0.2 27 5 10 um, rotmde. particle DN'tH(17.9) of nll rouned Plte Addition f 5t'.HPCmy im2prove 23 DC5:65 I 1.0 5- 20.0 .1 90 70 30 0.2 90 2IS like particles 2 um, dissolution furthter. Small palticles 24 3 56 5 V/v 1 51 200 0.2 130 60 25 0.2 81 15.3 aggloneralion particle morphalo changes Tuthle 13 Com ound ond P-237 j 9 ljj .ln. I PPs I.1 4 el hi~)Pril C. (%iDri Flow OI M~ ftdi Size ShelS) IVLI IIPMC fI mln V1 jmn) L-_m I &t pholouVy I Deycirlsiton Comment Polona#me did not precipitate under r-r r~ I I I I I son Al I 500 I ti I Z DlM l.V U:fu' It odtos 70:01. Non-uniform plalen and angular Severe nozzle blockages. Low Yield.

26 DC&I 2.5 (030 18.0 0A 100 135 1200 0.2 36 18 particles up to 30 ummtinie 27(71.3 1009 18.0__ 0. -0 -507 Non-uniforti Plates and angular Large nozzle lip to reduce nozzle 27 0M 17 1001) 1.0 0I 10 35 35 05 664 particles up to 10 urn in size blockinX Cocnuation reduced.

Nojinnrform plates and angular Increase solution flow to reduce ooze 28 23CN 1.75 100:0 18.0 U.2 100 35 80 0.73 58 6. putce pt 0 run in size blucka es.

-CN 1-01. 0 5 5 7 1 Largo non-cni rn~ duarls up No nozzle tip.

29 ICI 17 0: 80 2 10 3 06 i to 20 urn in size 30 CM 2.0 101 to .2 90 0 00 02 2 D Clusters of small rounded Tmstperule too high to proces ICI 20 100 1. .2 9 0 20 0 2 5 part icles <2I urn polaxamet.

DCM___ 1. -90 01 7 5 6 5 1 Clusters of sma rounded Reduced T P. solution contc. and 32 IC 2. 10. 280 01 7 5 6 2 74Particlesa 2aum flowv rate to get smallcr Particles 32 DM 10 7n:30 180 01 7 5 4 2 10 cutr rmopae m Irtrodudion of polotcamkT changes 32_ (7C.1 2.-m 5 3 5 028 9 lsesaaml lts< r orphtology' and particle size.

33 DCMl 1.0 50:50 18.0 0.1 75 35 45 0.2 59 Agglomerated large platea Very agglornesated sample 34 DCM% 2.0 20:80 18.0 0.1 75 35 40 0.2 4 Agglomerated pouoamerpltes Parice re oza c o preciptata 3 N 10 70:30 i 0 73 3 0 02 2Clsesopltsuto0Um Solution flow Iicreased to get highter 0C 20 (747) 1~ 2 7 5 4 7Catsfpaeut2 r thsroughput. Yield reduced.

36 -N 1:5 1. 5 3 5 2 8 1. lseso M1 lts<8u Particles appear clustered ratherttan 3 CI 3.0 100H:0 18.0 0.2 90 68 350 0.2 75 4.5 Run abandoned midway due Lu 37 0CMextreme nozzle blockcages.

-Well deflned rudd±d particles Repeat ofrut 32 but tlvoughpct 38 0CM 2.0t 100:0 18.0 015 75 35 1 150 0.2 92 2.0 2ur. No aggoreration increased.

391M 0 18.- 0.1 75 3 -5 0 2 Well delined rounded Particles Repeat of run 38 to produze a larger 39 951 1C 2.180 02 5 3 5 2 8 <2urn. Nd aglomneration batch.

70:3D__ 1 0-1 75 3 -2 0 0 252 A ggloincratied plates up to W ide size distrib uition. Particlasiza 0CM zo 70:30 18 1 5 75 3120 0 5 2.0 urn in sirn increase with moe poloxamcr.

41 wm 2. 0 (71:1 3) 1 1 7-3 7 .5 2. Agglomerated plates upl to M~sterial added to run 40 materiali.

41 3CM 2.0 7030 28 0.5 7 5 10 02 9 21 20 urn in size 42 DCNI 2.0 50:50 18.0 0.25 75 35 200 0.2 77 32.4 ourn inie ltsporT Pilesawine as i 4 85:15 0.-7 5 10 6 1. Agglorraatdtd plates up to Particle size reduced with lowver 43 CM 2.0 (86.1 2 8.15 7 35 I 7 0. 96 u2. l n size pola rmetcnl Toble 16 Comilound 411) find UPC Run No.

1 3 4 6 Solvent 3 5:65 v/v DIXMEtOlI 35:65 v'v DCMINtICUI 3 5:6 5 v/v D)CN/Et()hl 35:63 v/v D)CM00IOI 33:65 viv

DCMJFIOI

35.65 v/v DCWEtOll 35:65 v/v Soln.Co'c- (wfv) Drug:Polyttiw (Polym. Type) 1001:0 1.0 1.0 10 C02 Flow 20 20 20 20 20 20 Solo.

Flow (ml/min) 0.1 0.1 0.2 0.U pressure (bar) 90 90 120 I2O 130 120 Tamp 70 70 60 [50 5 0 Nozzle 02) Size 200 02 110 0.2 140 0.2 20n 0.2 250 0.2 60 02 Yield 74 66 78 64 39

SI

Particle Size SEM Deasttjol/MopoloK2

VMD

4. 1Sal disree rounded/grarulat 4.0 Sma pesidcs lightly aggregaled plateliktounded particles S Slightly larger tsirtded'Ignmular 41 Particles 6.6 Small irregular chunks Comments Fine powder, pliase-apit contions (similar to Compound (I) Meoll does not appear to help Marc angular particles produced with homogenous condh.-ons Chunk like p rticlea whh higher density COI Problem with BPR during run may have caused larger particles Reduced AP. Polymer and drug appear to CrYstallite separately Somne fiated patiles.

1.0 1.0 1.0 100:0 100:0 100:0 85:15 10.3 Dual morphology. Small 3umn end larger aaicar OIPC) particles 95:15 go 7o 1 150 1 0.2 al 4.6 Cluiter of runodgerantlar ISample appears to e a c- particles i Precipitate DCMIFOII O I Soe fparticlicle 33:65 v/v DCIt/EIOli 1.0 (Low MW HPC) 20 0. g i tt

K

DCM/EOII

to Acrdrne I Acamic 61:39 v/v 12 Acra~wte/Cyclrollexam: 13 Acdrne 1.0 1.15 1.73 1.2 2.0 85:15 (Law Mw 1IPC) 15:85 (I IPC) 20 (,PC 585 20 20 0

I

0.1 0.1 0.1 120 60 60 70 0.2 0.1 0.1 11.0 Dual morphology. Small 3 nm and larger acicular Particles Small primary particles <4 urn 120 60 0 120 60 I 2 Salpiy arties/I<i4edm reavl cgreclatefs.

Tml rry particles ur havpiy artie/ls <d.u h eal sligr.tdlsc SmlTrimae oprtcicl< n Preciptte Reduced P. Polymer and drug appear to crystallise separately (S0 nil vessel). Stringy polymer mass n nozzle tip white powder covering erttire vessel (300 ml vessel). Coarse whitea powder covering atire vessel. Poor yield 20:80 20 20 9-0 70 36.3 10 0.1 61 36.3 havpiy aeid/um Tn,. laggnrwcdfltce wle pow'der covering atire vessel I I True__

C-,

w 0

C

0

CO

Run No.

14 1S 16 17 19 21 22 23 24 Solvent Aedone Aceonae Acotone Acduine 35:65 v/v DCMfE1OH Acet one 20:55 v'v Accluse/Cyc1Oi lexamie Acdone Acetone 35:65 ./v DUM/EtOll Actons Sobn.Conr- 2.1 2.1 2.0 2.0 2.0 1.0 2.0 1.3 2.0 2.0 1.0 20 Table 17 Compnound (11) and HPC (coutd) C02 Sois. Pflfe Tm P Nozl s (Polym. Type) (mI/nun) (mI/mm) (ar C) a) (mm) 30:70 20 0.1 150 50 >200? 0.1 31 (LOW Mw IIPC) 30:70 20 0.1 120 60 20 0.2 9( (,0W MW 11TC) 2:5 200 1.0 120 60 5 0.2 6

(IIPC)

25:75 200 1.0 120 60 5 0.2 6 30:70 200 10 120 60 15 0.2 6 (IlPC) 90.10 2001 1.0 90 50 60 0.2 7 (1IPC) 50:50 200 1.0 120 60 20 0.2 (IIpC) 2080 200 1.0 75 35 5 0.2 (P237) 50:50 200 1.0 s0 35 30 11.2 (P237) 70:30 2M( 3.0 120 60 60 0.2 (I IPC) 90:10 200 1.0 90 52 45 0.2

(IIPC)

10:90 200 1.0 120 60 5 0.2

(IIPC)

Particle d Size

VMD

3 37.9 2 12.0 2 47.1 1 7.9 6 33.7 10 t0 50) 13.4 SEM DescriPtionlIMwIholOV' Small prmay particles S um heavily agiregatedlifed.

True co-procipitate Small primary particles 5 urn heavily aggregated/firsed.

True co-preeiPitate Small primary partile S um Ieavily ggreg atcd ius ed.

True co-precipitale Dual mrphology. Small paticles 4 urn and thin wrer like Plates.

Dual ninrplnlogy. Small particles 2 urn but o stly tin wafer like plat..

Smaill primary paties 3 1111 heavily aggregtedtirsed.

Appeas to be CO-Preclpitatc Agglonlegated/tssed irregular shaped dchunks Small pns" paties 3 urn heavily aggzepte6'lirsed.

Comments o (500 mli vessel). Coarsewhite powder oovering; entire vessel. Problem with trs(A??) (50 ml vessel). Stringy polymer mass on nozzle tip PilLt Plant. Coaroeffibrous powder covestig vessel walls Pilot Plant. Cuarse/fflrous powder covering vessel walls Pilot Plant. Coartefibrors powder covering vessel Walls Pilot plant. IA&lu, flully powder covering whole vessel Pilot Plant. Coarseilibrots powder covering vessel wails Pilot Plant. Thin white film coating Walls.

Pilot Plant. Thin white powder film coating walls.

Pilot Plant. Ugltt, Irfy powder covering whole yasse Dual morphology. Small Pilot Plant. Ught, fluffy 55 6.7 partidles 2 umr but molly thin powder covering whole j wafer likeplates. vessel P ilet Plant. Coarsellibrous 63 >10 Small primary Particles 3 um odr oenngvse v3iey heavil ggregated/i'ued. ,decorigvsl WO 01/15664 WO 0115664PCT/GB00103328 References I Ford, (1986) The Current Status of Solid Dispersions. Phwrm. Acta Helv 61(3), 69-88.

2 Yoshioka Hancock, B.C. and Zografi, (1995) Inhibition of Indomethacin Crystalisation in Poly(vinylpyrrolidotie) Coprecipitates. J Pharm. Sci. 84(88 983-986.

3 Yoshioka, Hancock, B. Zografi, G. (1995) Crystallization of Indomethacin from the Amorphous State below and above its Glass Transition Temperature J Pharmn. Sci. 83, 1700-1705.

4 Byrn, S. Pfeiffer, R. R_ and Stowell, J. G. (1999) Solid-State Chemnistry of Drugs, Second Edition SSCI Inc., West Lafayette, Indiana, USA, 249-258.

Serajuddin, A. T. M. (1999) Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems and Recent Breakthroughs. J Pharm Sci. 88(10 1058-1066.

6 Matsumoto, T. and Zografi, G. (1999) Physical Properties of Solid Molecular Dispersions of Indoniethacin with Poly(vinylpyrrolidofle) and Poly(vinylpyrTolidofle-co.vinylacetate) in Relation to Indomethacin Crystallisation, Pharm. Res. 16011) 1722-1728.

7 Brocchini, Synthetic Polymers for Drug Delivery Applications, World Markets Series "Business Briefing", Pharma Tech, Drug Delivery Supplement, May 2000,216-221.

8 Sakellarioti, and Rowe, (1995) Interactions in Cellulose Derivative Films for Oral Drug Delivery. Pro. Polym. Sci., 20, 889-942.

9 Hancock, York, P. and Rowe, R. C. (1997) The Use of Solubility Parameters in Pharmaceutical Dosage Form Design. Int. J Pharm. 148, 1-21.

Romero Reillo Escalera B. and Bustamente The Behaviour of Paracetamol in Mixtures of Amphiprotic and Amphiprotic-Aprotic Solvents.

Relationship of Solubility Curves to Specific and Nonspecific Interactions 1996, Chem.

Pharm. Bull. 44(.5. 1061-1064.

11 Subrahmanyam C. V. Sreenivasa Reddy Venkata Rao J. and Gundu Rao Irregular Solution Behaviour of Paracetamol in Binary Solvents, 1992, Int. J. Phar.

78(1992) 17-24.

12 Barra Lescure Doelker E. and Bustamente The Expanded Hansen Approach to Solubility Parameters. Paracetamol and Citric Acid in Individual Solvents, 1997, J. Pharm. Pharmacol 49 644-651.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, S. an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

*•o *go *o~ oo

Claims (1)

1. Claims

   1 A coformulation of an active substance and an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, wherein the amorphous phase active substance is stable, with respect to its crystalline form(s) for at least three months after its preparation when stored at between 0 and 10°C, provided that when the active substance is indomethacin, the polymer is not poly vinyl pyrrolidone.

   2 A coformulation of an active substance and an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, wherein the amorphous phase active substance is stable, with respect to its crystalline form(s) for at least six months after its preparation when stored at between 0 and 10°C.

   3 A coformulation according to claim 1 or claim 2, wherein the amorphous phase active substance is stable for at least twenty four months after its preparation, when stored at between 0 and 10°C.

   4 A coformulation according to claim 1, claim 2 or claim 3, wherein the amoφhous phase active substance is stable for the specified storage period, when stored at 25°C.

   5 A coformulation according to any one of the preceding claims, wherein the active substance comprises a pharmaceutically active substance.

   6 A coformulation according to claim 5, wherein the active substance is selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid.

   7 A coformulation according to claim 5, wherein the active substance is a COX-2 selective inhibitor. 8 A coformulation according to claim 7, wherein the COX-2 selective inhibitor is a diarylheterocycle.

   9 A coformulation according to claim 7, wherein the COX-2 selective inhibitor is selected from the group consisting of (Z)-3-[l-(4-bromophenyl)-l-(4- methylsulfonylphenyl)methylene] dihydrofuran-2-one, (Z)-3 -[1 -(4-chlorophenyl)- 1 -(4- methylsulfonylphenyl)methylene] dihydrofuran-2-one, 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide, 4-[4-(methylsulfonyl)phenyl]-3- phenyl-2(5H)-furanone and the compound of Formula (HI):

   10 A coformulation of (i) an active substance selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid and (ii) an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amoφhous as opposed to crystalline form, and in which the active substance represents at least 10% of the coformulation, provided that when the active substance is indomethacin or theophylline, the oligomeric or polymeric material is not poly vinyl pyrrolidone.

   11 A coformulation according to any one of the preceding claims, wherein the oligomeric or polymeric material is selected from the group consisting of cellulosic materials (including cellulose derivatives), vinyl polymers, poly lactic or glycolic acids (including lactide/glycolide copolymers), and mixtures thereof. 12 A coformulation according to any one of the preceding claims, wherein the active substance is a polar substance and the oligomeric or polymeric material is hydrophobic.

   13 A coformulation according to any one of the preceding claims, wherein 100% of the active substance is present in an amoφhous as opposed to crystalline form.

   14 A coformulation according to any one of the preceding claims, wherein the active substance represents at least 20% of the coformulation.

   15 A coformulation according to any one of the preceding claims, comprising an intimate single-phase mixture of the active substance and the oligomeric or polymeric material, from which the dissolution rate of the active substance in an aqueous medium is no higher for the first 30 minutes than it is subsequently.

   16 A coformulation according to claim 15, wherein the dissolution rate of the active substance in an aqueous medium is no higher for the first 60 minutes than it is subsequently.

   17 A coformulation of paracetamol and an oligomeric or polymeric material, in which between 80 and 100% of the paracetamol is present in an amoφhous as opposed to crystalline form, and in which the paracetamol represents at least 1% of the coformulation.

   18 A coformulation according to claim 17 wherein 100% of the paracetamol is present in an amoφhous form.

   19 A coformulation according to claim 17 or claim 18, wherein the paracetamol represents at least 25% of the coformulation. 20 A coformulation according to any one of claims 17 to 19, wherein the amoφhous phase paracetamol is stable, with respect to its crystalline form(s) for at least three months after its preparation, when stored at between 0 and 10°C.

   21 A coformulation according to any one of the preceding claims, which has been prepared by a SEDS™ process.

   22 A coformulation of an active substance and an oligomeric or polymeric material, according to any one of claims 1, 2, 10 or 17, the coformulation being substantially as herein described with reference to the accompanying illustrative drawings.

   23 A pharmaceutical composition containing a coformulation according to any one of the preceding claims.

   24 A method for preparing a coformulation according to any one of claims 1 to 22, which method involves the use of a SEDS™ process.

   25 Use of a SEDS™ process to prepare a coformulation of an active substance and an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amoφhous as opposed to crystalline form, and in which the active substance represents at least 10% of the coformulation.

   26 A method for preparing a coformulation of an active substance and an oligomeric or polymeric material, using an anti-solvent-induced particle formation process, wherein, under the operating conditions used, the active substance is soluble in the chosen "anti-solvent" but the oligomeric or polymeric material is not.

   27 A method according to claim 26, wherein the particle formation process is a SEDS™ process.

   28 A method according to claim 26 or claim 27, wherein the anti-solvent is supercritical carbon dioxide. 29 A method according to any one of claims 26 to 28, wherein the active substance is ketoprofen.

   30 A method according to any one of claims 26 to 29, wherein the oligomeric or polymeric material is hydroxypropyl methyl cellulose.

   31 A method for preparing a coformulation of an active substance and an oligomeric or polymeric material, the method being substantially as herein described with reference to the accompanying illustrative drawings.