METHOD FOR MAKING PARENTERAL PHARMACEUTICAL COMPOSITIONS

Field of the Invention

The present invention relates to a method for making unit dose pharmaceutical products, especially pharmaceutical products suitable for parenteral administration.

Background of the Invention

Parenteral preparations often have more rigorous production and quality standards than other pharmaceutical dosage forms. These requirements result from the fact that parenteral products are injected directly into body tissue. Thus, these products must be exceptionally pure and free from contaminants, especially pyrogens.

A variety of parenteral drug delivery systems are under investigation, for example soluble and particulate delivery systems. Soluble delivery systems are available as ready to use solutions or reconstitutable powders in unit dose containers.

Manufacture of reconstitutable powders poses two particular problems: the filling of a unit dose container and the formation of nanoparticles that make up the powder.

Reconstitutable powders in unit dose containers are manufactured either by filling sterile powders into pre-sterilized unit dose containers under strict aseptic conditions or by filling of non sterile powders and terminally sterilizing them provided that the active ingredient can tolerate terminal sterilization (e.g., heat or irradiation).

Another method for making sterile reconstitutable powders is by lyophilization, or freeze-drying. Several commercial products are available based on these manufacturing methods. However, both processes, dry powder filling and lyophilization have limitations.

In the case of dry powder filling, powder contamination during the filling operation requires the need for dedicated manufacturing facilities (esp. for antibiotics) as lack of cross contamination is difficult to prove. Moreover, dusting during the filling operations increases the risk of explosion.

Lyophilization is a cumbersome and long process that must be conducted in batches. Lyophilization of solvents other than water is not widely used due to the need for specially designed equipment for organic solvent removal.

Nanoparticles are of particular interest since they have many different applications, such as for vascular delivery (e.g., targeting of macrophages, restenosis and angiogenic vessels), active and passive site specific targeting (e.g., solid tumors, osteoporosis and Alzheimer's), transfusion medicine (e.g., oxygen delivery and radiopharmaceutical imaging), gene and/or SiRNA delivery or stem cell delivery for a variety of diseases, sustained-release depot formulations to minimize frequency of injections and poorly soluble drugs to avoid unsafe cosolvent based systems. The available manufacturing processes to achieve such particulate systems are broadly classified as milling, homogenization and spray drying. The following table summarizes some of the challenges surrounding these aforementioned processes.

Process Issues Milling Homogenization Spray Drying flexibility for control of particle low medium medium characteristics particulate contamination potential high medium low process scale-up & validation complexity high medium low aseptic processing complexity high high high batch process yes yes yes platform process for aseptic processing no no no complexity of adaptability for process high high high analytical technology

Milling techniques are frequently used in industrial practice to reduce the particle size of solids. However, dry milling techniques may cause unacceptable levels of dust which require sophisticated safety precautions during milling. Moreover in many cases, dry milling increases the amorphous content in particulate formulations of therapeutic compounds, which may not be advantageous or entail weakened or even adverse therapeutic effects. Dry milling processes often also suffer from significant product loss or from operational

problems such as product caking or equipment clogging. The main limitation of wet milling technology is heavy metal and/or grinding media contamination due to direct physical contact of the particles with the grinding media, as well as wall attrition.

Spray and freeze drying techniques have been used as alternative processes to produce micronized dry powders. However, these technologies may produce inconsistent average particle sizes. Moreover, thermally labile molecules can be prone to decomposition or degradation upon exposure to elevated temperatures that are typically used in spray drying. Similarly, an often undesired increase of the amorphous content in the formulation is often observed in both spray and freeze drying.

Thus, there is need for processes that overcome these above described limitations related to manufacturing reconstitutable powders. The present invention features a manufacturing process and the equipment therefor that allows the filling of unit dose containers either with aqueous or organic solvent based solutions and further allows removal of such solvent causing a powder to precipitate in the unit dose container at the desired quantity, quality and particle size. The present invention features a processing method for filling unit dose containers through the use of supercritical fluids that not only allows for efficient filling but also size reduction of the drug compound in a unit dose container.

The use of supercritical fluids also provides additional advantages over other traditional means of manufacturing parenteral products. Supercritical fluids provide a means for controlling the particle size and shape of the therapeutic compound. This may be important for powderized therapeutic compounds that are formed into colloidal suspensions when a vehicle is added to the powder.

Furthermore, a smaller particle size minimizes the change for embolism.

Another possible advantage is that the design of nanoparticle architecture can be accomplished through extensive experimentation in the laboratory without any concerns of scale-up parameters since the lab scale may also be the production scale.

Unit dose containers/receptacles of different shapes, sizes and materials can be designed and used with the current invention. Processing conditions for each of the designs can be established using test equipment specially designed for this purpose.

In view of the progress in genomics and related areas, individualized therapy will be necessary in the future. However, the aforementioned processes are batch processes and are neither economical nor suitable for generating products for individualized therapy.

The current process addresses this significant limitation of the existing processes. For example, the equipment can also be used at independent clinics to generate particulate formulations of stem cells or genes etc. The existing processes also do not allow the synthesis of small molecule therapeutics in unit dose containers for individualized therapy. It is conceivable in the future, based on developments in genomics, that chemicals can be identified that are specific not only for certain receptors and disease but for specific individuals. Existing systems and processes do not offer the potential to synthesize in a pharmaceutically acceptable format drugs for such individuals. The current process, however, offers such a potential. The present invention is based on a processing method that utilizes supercritical fluids. In addition to using supercritical fluids for filling, the process equipment can also be used for synthesizing drugs in the unit dose containers.

Summary of the Invention

The present invention features a method of preparing a unit dose pharmaceutical composition for parenteral administration. The steps in this process include:

(a) dissolving a therapeutic compound in a solvent to form a solution;

(b) contacting this solution with an antisolvent; and

(c) precipitating the therapeutic compound as a powder.

The precipitation process may be accomplished by the use of supercritical fluid processes as known in the art. Examples of such processes include, but are not limited to, RESS, GAS, SAS and SEDS which are further detailed below.

In another aspect of the present invention, a collection vessel that is suitable for containing a pharmaceutical composition with a therapeutic compound is provided. The collection vessel features a porous frit that allows the precipitated pharmaceutical composition to be maintained within the collection vessel while the solvent and antisolvent used to precipitate the powder exit the collection vessel.

Brief Description of the Drawings

FIG. 1 shows an exemplary vial that can be used in an exemplary embodiment of the present invention for filling unit dose containers.

FIG. 2 provides a general schematic of an apparatus used to implement an exemplary embodiment of the present invention for filling unit dose containers.

FIG. 3 provides a more detailed cross-sectional view of the nozzle section of the apparatus in FIG. 2.

FIG. 4a provides a side cross-sectional view of an exemplary coaxial nozzle section for use in the apparatus of FIG. 2.

FIG. 4b provides a front cross-sectional view of the coaxial nozzle section in FIG. 4a.

Detailed Description of the Invention

The present invention features a method for filling unit dose containers of a dry powder therapeutic compound for parenteral administration using supercritical fluid technology. By adjusting the filling parameters, the particle sizes of the powder can also be controlled (e.g., to form nanoparticles).

As used herein, the term "parenteral administration" means an injection administered by routes, such as intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraocular, intracranial, intrathecal or to any other body part or tissue.

As used herein, the term "pharmaceutical composition" means finely dispersed solid particles that contain a therapeutic compound that can be administered to a mammal, e.g., a human in order to prevent, treat or control a particular disease or condition affecting the mammal. The pharmaceutical composition can be subsequently mixed with a pharmaceutically acceptable vehicle to form a dispersion or solution appropriate for parenteral administration.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without

excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

As used herein, the term "therapeutic compound" means any compound, substance, drug, medicament or active ingredient having a therapeutic or pharmacological effect, and which is suitable for administration to a mammal, e.g., a human, in a composition that is particularly suitable for parenteral administration. The therapeutic compound can be a small molecule, a biomolecule or cells (including stem cells). A biomolecule is, e.g., a molecular moiety or fragment of DNA, RNA, antisense oligonucleotides, peptides, polypeptides, proteins, ribosomes and enzyme cofactors.

Examples of therapeutic classes of therapeutic compounds include, but are not limited to, antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, antimanics, stimulants, antihistamines, anti-cancer therapeutic compounds, laxatives, decongestants, vitamins, gastrointestinal sedatives, antidiarrheal preparations, anti-anginal therapeutic compounds, vasodilators, antiarrythmics, anti-hypertensive therapeutic compounds, vasoconstrictors and migraine treatments, anticoagulants and antithrombotic therapeutic compounds, analgesics, antipyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular therapeutic compounds, hyper-and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity therapeutic compounds, anabolic therapeutic compounds, erythropoietic therapeutic compounds, anti-asthmatics, expectorants, cough suppressants, mucolytics, anti-uricemic therapeutic compounds.

Exemplary therapeutic compounds include, but are not limited to, gastrointestinal sedatives, such as metoclopramide and propantheline bromide; antacids, such as aluminum trisilicate, aluminum hydroxide and cimetidine; anti-inflammatory therapeutic compounds, such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator therapeutic compounds, such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral and cerebral vasodilators, such as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid; anti-infective therapeutic compounds, such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucolaxacillin sodium, hexamine mandelate and

hexamine hippurate; neuroleptic therapeutic compounds, such as fluazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine; central nervous stimulants, such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride; anti-histamic therapeutic compounds, such as diphenhydramine, diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrheal therapeutic compounds, such as bisacodyl and magnesium hydroxide; laxative therapeutic compounds, such as dioctyl sodium sulfosuccinate; nutritional supplements, such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine; anti-spasmotic therapeutic compounds, such as dicyclomine and diphenoxylate; therapeutic compounds effecting the rhythm of the heart, such as verapamil, nifedepine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate; therapeutic compounds used in the treatment of hypertension, such as propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; therapeutic compounds used in the treatment of migraine, such as ergotamine; therapeutic compounds effecting coagulation of blood, such as epsilon aminocaproic acid and protamine sulfate; analgesic therapeutic compounds, such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid; anti-epileptic therapeutic compounds, such as phenytoin sodium and sodium valproate; neuromuscular therapeutic compounds, such as dantrolene sodium; therapeutic compounds used in the treatment of diabetes, such as metformin, tolbutamide, diabenase glucagon and insulin; therapeutic compounds used in the treatment of thyroid gland dysfunction, such as triiodothyronine, thyroxine and propylthiouracil; diuretic therapeutic compounds, such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and triampterene; uterine relaxant therapeutic compounds, such as ritodrine; appetite suppressants, such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride; anti-asthmatic therapeutic compounds, such as aminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate, expectorant therapeutic compounds, such as guaiphenesin; cough suppressants, such as dextromethorphan and noscapine; mucolytic therapeutic compounds, such as carbocisteine; anti-septics, such as cetylpyridinium chloride, tyrothricin and chlorhexidine; decongestant therapeutic compounds, such as phenylpropanolamine and pseudoephedrine; hypnotic

therapeutic compounds, such as dichloralphenazone and nitrazepam; anti-nauseant therapeutic compounds, such as promethazine theoclate; haemopoetic therapeutic compounds, such as ferrous sulphate, folic acid and calcium gluconate; and uricosuric therapeutic compounds, such as sulphinpyrazone, allopurinol and probenecid and the like.

Especially useful in the present invention are therapeutic compounds that are suitable for parenteral administration.

The therapeutic compound(s) is present in the pharmaceutical compositions of the present invention in a therapeutically effective amount or concentration. Such a therapeutically effective amount or concentration is known to one of ordinary skill in the art as the amount or concentration varies with the therapeutic compound being used and the indication which is being addressed. For example, in accordance with the present invention, the therapeutic compound may be present in an amount by weight from about 1% to about 100% by weight of the pharmaceutical composition. For example, in case of synthesis of chemical drug substances by means of supercritical fluids, 100% by weight will be the desired outcome. For the delivery of nanoparticulate formulations, depending on the potency of the drug, the necessary dosing requirements etc., the weight fraction is established on a case by case basis as is known to one of ordinary skill in the art.

The pharmaceutical compositions can also further include pharmaceutically acceptable carriers, adjuvants, stabilizers, preservatives, dispersing agents, surfactants and other agents conventional in the art having regard to the type of formulation in question. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers, such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts; antioxidants, such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid or arginine; monosaccharides; disaccharides; and other carbohydrates including cellulose or its derivatives, glucose, manose or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; counterions, such as sodium; and/or nonionic surfactants, such as polysorbates, poloxamers or PEG. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the parenteral dosage form by routine experimentation and without any. undue burden. The amount of each excipient used may

vary within ranges conventional in the art. The following references which are all hereby incorporated by reference discloses techniques and excipients used to formulate parenteral dosage forms. See The Handbook of Pharmaceutical Excipients, 4 ^th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20 ^th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).

As used herein, the term "unit dosage" or "unit dose" refers to the quantity of pharmaceutical composition needed to provide a single administration of the therapeutic compound. This quantity, e.g., is packaged in a single package, e.g., a vial or unit. When needed, a healthcare practitioner can administer the contents of a single package, i.e., the unit dosage or unit dose, parenterally to a patient in need thereof.

As used herein, the term "microparticles" refers to particles having an average particle diameter in the range of about one to five hundred microns, e.g., about one to about ten microns. As used herein, the term "nanoparticles" refers to particles having an average particle diameter in the range from about 0.001-1 micron, e.g., about 0.05 micron to about 0.5 microns.

As used herein, the term "supercritical fluid" refers to a fluid at or above its critical pressure (P _c ) and critical temperature (T ₀ ), simultaneously. Thus, a fluid above its critical pressure and at its critical temperature is in a supercritical state. A fluid at its critical pressure and above its critical temperature is also supercritical. As used herein, supercritical fluids also encompass both near supercritical fluids and subcritical fluids. A "near supercritical fluid" is above but close to its P _c and T ₀ , simultaneously. A "subcritical fluid" is above its P _c and close to its T _c .

As used herein, the term an "antisolvent" refers to a supercritical fluid.

Any material can be used as the supercritical fluid provided that material is suitable for processing under the specific operation conditions contemplated herein. Examples such materials that can be compressed into a supercritical fluid include, but are not limited to, carbon dioxide, methane, benzene, methanol, ethane, ethylene, xenon, nitrous oxide, fluroform, dimethyl ether, propane, n-butane, isobutane, n-pentane, isopropanol, methanol, toluene, propylene, chlorotrifluro-methane, sulfur hexafluoride, bromotrifluromethane, chlorodifluoromethane, hexafluoroethane, carbon tetrafluoride, decalin, cyclohexane, xylene, tetralin, aniline, acetylene, monofluoromethane, 1 , 1 -difluoroethylene, ammonia, water and

mixtures thereof. Particularly useful is carbon dioxide which has a T _c of 31.1 °C and a P _c of 7.38 MPa.

Various processes for particle formation exist based on supercritical fluid technology (such processes are hereinafter termed "supercritical fluid process"). Examples of such supercritical fluid processes include, but are not limited to, rapid expansion of supercritical solutions ("RESS"), gas antisolvent precipitation ("GAS"), supercritical anti-solvent ("SAS") and solution enhanced dispersion by supercritical fluids ("SEDS"). See, e.g., Jennifer Jung et al., "Particle design using supercritical fluids: Literature and patent survey", J Supercrit Fluids, Vol. 20, pp. 179-219 (2001), which is hereby incorporated by reference.

Each of the aforementioned supercritical fluid processes uses a solvent. As used herein, the term "solvent" refers to a material that is able to dissolve, disperse and/or solubilize the therapeutic compound of interest (e.g., solubility of the drug in the solvent from about 0.01-50% w/v, e.g., 0.1-10%, e.g., 1-5%). A solvent can consist of a single material or a mixture of materials. Modifiers or co-solvents to enhance the dissolution, dispersion and/or solubilization of the therapeutic compound can also be added to the solvent.

Examples of classes of solvents include, but are not limited to, alcohols, ethers, ketones, esters, alkanes, halides or mixtures thereof. Examples of solvents include, but are not limited to water, ammonia, dimethylsulfoxide, methanol, ethanol, isopropanol, n-propanol, methylene chloride, acetone, ethylacetate, tetrohydrofuran, ethyl ether or mixtures thereof.

The RESS process, e.g., involves the dissolution, suspension and/or solubilization of the therapeutic compound and any optional pharmaceutically acceptable excipients in a supercritical fluid to form a homogenous solution. As used herein, the term "solution" may also refer to a mixture if the therapeutic compound and/or the pharmaceutically acceptable excipients are suspended in the solvent. The solution is then depressurized by passing through a heated orifice or nozzle into a low pressure, e.g. atmospheric chamber. When the solution depressurizes, the supercritical fluid vaporizes leaving the substrates (i.e., the pharmaceutical composition) in the form of particles.

The SAS process, also known as PCA (precipitation with compressed anti-solvents) uses a solvent and an antisolvent. In this process, the therapeutic compound and any pharmaceutically acceptable excipients are, e.g., dissolved, suspended and/or solubilized in

a solvent to form a homogeneous solution. The solvent is miscible with the supercritical fluid. The solution is then mixed with the supercritical fluid. The supercritical fluid causes the solvent to expand resulting in a lower solvent strength than the pure solvent. The mixture becomes supersaturated and the substrate precipitates. The mixing is accomplished through the use of particular nozzle designs, which can be varied, and the particle size and morphology of the therapeutic compound can be controlled by varying the pressure and temperature prior to spraying the solution into the collection chamber, as well as by varying the flow rate ratio between the two streams entering the collection vessel through the nozzle, i.e., the solution and antisolvent flow rates.

The GAS process is similar to the SAS process; however, the supercritical fluid is added to a solution of the therapeutic compound dissolved, suspended and/or solubilized in an organic cosolvent. The supercritical fluid and solvent are miscible whereas the therapeutic compound has limited solubility in the supercritical fluid. The supercritical fluid functions as an antisolvent to precipitate particles of the therapeutic compound.

As with the GAS and SAS processes, the SEDS process features the therapeutic compound and any optionally pharmaceutically acceptable excipients dissolved, suspended and/or solubilized in a solvent to form a solution. The solution and the supercritical fluid are each passed through an orifice or nozzle and sprayed into a pressurized collection chamber. The two orifices or nozzles can be arranged separately or co-axially. The high velocity of the supercritical fluid disrupts the solution into very small droplets. Additionally, the conditions are such that the supercritical fluid extracts the solvent from the solution as the supercritical fluid and solution contact each other. Like the preceding processes, as the solvent is extracted, the pharmaceutical composition remains.

Used with the supercritical fluid processes of the present invention is a unit dose container that serves as the primary packaging of the pharmaceutical composition. Primary packaging refers to the packaging that is in physical contact with the pharmaceutical composition, as opposed to a box or carton that can serve as secondary packaging to house the primary packaging.

Any type of primary packaging, or vessel, known in the art for use with parenteral products, e.g., vials and ampoules, can be used in the present invention. Such known primary packaging can be adapted or modified for use within the present invention. FIG. 1

features an axial cross-sectional view of an exemplary embodiment of a vial that can be used with the present invention. Vial 10 features a cylindrical container wall 20 with two ends that define a first opening 30 and a second opening 40. Located at each opening is a first seal 32 and a second seal 42 (e.g., made of aluminum). Towards the ends of the vial 10, the container wall 20 tapers inwardly to form a first shoulder 34 and a second shoulder 44. Disposed transverse (e.g., perpendicular) to the axis A of the vial 10 is a porous filter 50 (i.e., frit). The porous filter 50 divides the interior of the vial 10 into an upper chamber 52 and lower chamber 54. The volume of the chambers 52 and 54 can be equal or different, with one chamber, e.g., 52, being larger or substantially larger than the other chamber, e.g., 54. Note that the filter 50 can be arranged at any angle to axis A provided that it covers any horizontal cross-section of the vial 10.

The vial, e.g., can be made of any conventional materials used for storing parenteral formulations, e.g., glass, such as borosilicate glasses, soda-lime treated glasses and soda- lime glasses; and plastic (e.g., polymers) (e.g. Daikyo Resin CZ available from West Pharmaceutical Services of Louisville, Kentucky; other polyolefins, polypropylene, polyethylene, PVC). Another possible material for the vial may be metal. The vial 10, e.g., has an outer diameter of about 25 mm and a height of about 88 mm. The filter 50, e.g., can be made of glass (e.g., fritted glass), porcelain, polycarbonate or other suitable material. The apertures in the filter 50 should be such that particles of the pharmaceutical composition are prevented from passing through the filter. The apertures can range in size from about 0.05-5 microns. For example, if the pharmaceutical composition has a mean size in the range from about 1 micron to about 5 microns, the filter can have apertures in the range from about 0.2-5 microns, e.g., 0.8 microns.

In addition to compatibility with the pharmaceutical composition, the vial 10 should also be able to withstand filling pressures generated by the filling using the supercritical fluid process. Such pressures may depend on the nature of the supercritical fluid used for the filling. For example, the container wall 20 should be able to withstand a pressure change of at least 600 psig (approx. 41 atm), and the filter 50 should be able to withstand a pressure change of at least 300 psig (approx. 20 atm).

FIG. 2 provides an exemplary flow diagram for the inventive process of the present invention. In apparatus 100, the therapeutic compound is dissolved and uniformly mixed in a solvent to form a solution 102 in vessel 104. In vessel 108 is the antisolvent, or supercritical

fluid 110, for example carbon dioxide. The solution 102 and supercritical fluid 110 can each be optionally pumped by pumps 112a and 112b through sterilizing filters 114a, 114b. The pumps 112a and 112b can maintain the fluids at the desired pressure. The desired temperature of the solution 102 and supercritical fluid 110 can be adjusted and maintained by equipment known to one of ordinary skill in the art, e.g., by thermocouples, heat exchangers, coolers and heaters. After the optional filtration, the solution 102 and supercritical fluid 110 are combined in nozzle section 116. Any type of nozzle can be used for the nozzle, e.g., a capillary nozzle, a convergent nozzle, a coaxial nozzle or an ultrasonic nozzle. The rates that the solution 102 and the supercritical fluid 110 enter the nozzle section can be independently adjusted. The supercritical fluid 110 diffuses into the solution 102 causing the therapeutic compound to precipitate into a vial 118 (e.g., the exemplary vial 10 of FIG. 1). The combined fluid stream 120 of the solvent from the solution 102 and the supercritical fluid 110 passes out of the vial 10 without the precipitated therapeutic compound which is held back by the filter 50 in the vial 118. The fluid stream 120 passes through a conventional separator 122 which separates the solvent from the supercritical fluid. Each of these materials can then be recycled back to the original vessels 102 and 108.

FIG. 3 shows a cross-sectional axial view of an exemplary nozzle section 118 and vial 120 releasably mounted in a holder 122. The vial 120 serves as the collection vessel and primary packaging of the pharmaceutical composition. The nozzle section 118, e.g., has two nozzles, 202 and 204, which extend into the interior 206 of the vial 120. The nozzles 202 and 204 are in fluid communication with the solution and supercritical fluid respectively. The nozzles 202 and 204 can be arranged parallel to each other or in a coaxial fashion. The solution and supercritical fluid exit the nozzles 202 and 204 simultaneously such that the supercritical fluid diffuses into the solution. The therapeutic compound precipitates from the solution as particles, e.g., microparticles or nanoparticles. The supercritical fluid and solvent continue to flow through the filter 208 and into conduit 210 which leads to a conventional separator (not shown). The filter 208 prevents any particles of therapeutic compound from entering the conduit 210. Once the therapeutic compound particles have been formed, the vial 120 can be ejected from the apparatus. Additionally, the ends of the vial 120 can be stopper with a rubber stopper, e.g., a coated rubber stopper, prior to sealing. The ends of the stoppered vial 118 can be sealed, e.g., with aluminum, seals; thus, resulting in a unit dose package.

FIGS. 4a and 4b show a side cross-sectional view and a front end cross-sectional view of an exemplary co-axial nozzle 300 for use in the present invention. The inner passage 302 carries the therapeutic compound dissolved in a solvent, and the outer passage 304 carries the antisolvent.

The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention.

Example 1

In a first experiment, the equipment, e.g., shown in FIGS. 2 and 3, are set up for a SAS spray process. This equipment is arranged such that the solution and antisolvent are introduced into the collection chamber or vial. The vial prior to the introduction of the solution and antisolvent has been pressurized with pure carbon dioxide through two different capillaries each having a drilling. The inner diameter of the drillings are about 1/16" and are slightly includes to allow the streams of solvent and antisolvent to meet inside the vial.

Three hundred (300) mg of paracetamol are dissolved in 2 g of analytical grade acetone to form an 80% saturated solution (c/c _sat =0.8). The vial is immersed in a water bath having a temperature of about 47°C. The pressure is maintained at 95 bar.

Supercritical carbon dioxide is used as the antisolvent. The flow rate of the antisolvent is set at about 10 g/min. The solution is introduced into the vial at a flow rate of about 0.5 mL/min.

After all of the solution is consumed, any residual solvent is removed from the equipment (i.e., system) by flushing with pure make-up carbon dioxide for 30 minutes while maintaining pressure and temperature at 95 bar and 47°C, respectively. The pressure is then released carefully. About 276 mg of paracetamol is harvested in the vial corresponding to a yield of 90.8%.

Examples 2 and 3

Compound I, shown below, is used for Examples 2 and 3:

Compound I

In Example 2, the same experimental set-up as disclosed in Example 1 is used. Thirteen hundred (1 ,300) mg of Compound I are dissolved in 1.2 g of ethanol p. a. to form the solution. Pressure and temperature are set at 100 bar and 50 ⁰ C, respectively. Once again, supercritical carbon dioxide is the antisolvent. The flow rates for the solution and antisolvent flow rates are 0.5 mL/min. and about 15 g/min., respectively. Approximately 254 g of a dry powder of Compound I are collected corresponding to a yield of 84.1%.

In Example 3, the same experiment is repeated with the exception that 304 mg of Compound I is dissolved in 1.2 g of ethanol p.a. to form the solution. About 276 g of a dry powder is collected corresponding to a yield of 90.1%.

In each of the Examples 1-3, the powder contains clumps and appears chunky. Moreover, the powder also adheres to the inner wall of the vials.

Examples 4 and 5

Additional experiments, Examples 4 and 5, are run with a change in the nozzle configuration to achieve better mixing and atomization. Examples 4 and 5 use a co-axial nozzle. The diameters of the co-axially arranged inner and outer capillaries are 1/16" and 1/8", respectively. The annulus of the nozzle is 0.05 mm. The inner passage carries the solution and the outer passage carries the antisolvent.

In Examples 4 and 5, a frit is used to capture the precipitating particles instead of a vial. However, it is possible to allows the solvent and antisolvent to stream into and mix in a collection vial containing a frit thereby allowing the particles to be precipitated and captured on the frit and within the vial.

In Example 4, 504 mg of Compound I is dissolved in 2 g of ethanol p. a. Pressure and temperature are maintained at 100 bar and 50 ⁰ C, respectively. The solution and antisolvent flow rates are 0.2 mL/min. and about 15 g/min., respectively. The resulting powder is no longer chunky but appears as a fine powder.

In Example 5, the experiment in Example 4 is repeated except that 501 mg of Compound I is dissolved in 2 g of ethanol p. a. A fine powder is obtained after precipitation.

It is understood that while the present invention has been described in conjunction with the detailed description thereof that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the following claims. Other aspects, advantages and modifications are within the scope of the claims.