Abstract Image

Drug shortages have become a growing and critical problem in America and worldwide. In 2011, there was a record high of 267 new prescription drug shortages.(Schoen, D.The Drug Shortage Crisis in America; ) According to the Food and Drug Administration (FDA), the leading primary reasons for the shortages are problems at the manufacturing facility (43%), delays in manufacturing or shipping (15%), and active pharmaceutical ingredient (API) shortages (10%).(A Review of FDA’s Approach to Medical Product Shortages; U.S. Food and Drug Administration: Silver Spring, MD,
On the other spectrum, military bases need to store large amounts of drugs to prepare for unpredictable crises such as war. This can lead to a significant waste of drugs, particularly the drugs with short shelf-life.
To overcome these issues, a new framework for pharmaceutical engineering that revolutionizes the supply chain and the manufacturing framework is needed.
One potential solution to this problem is a portable compact manufacturing system that can produce both APIs and final drug product. The realization of such a compact platform requires innovation in chemical synthesis, separation processes, automation, and process control. This contribution focuses on the final crystallization, filtration, and drying of the API prior to formulation.
Due to the compact nature of the proposed system, the hardware is not readily available in the market. This unavailability is both a challenge and an opportunity to review the pharmaceutical crystallization process to allow for potential improvement to existing technology or to intensify multiple unit operations to overcome the restriction in size.

Process for increasing the level of crystallinity and modifying surface characteristics in an amorphous solid material. The present invention has application in the manufacture of chemicals, such as active ingredient compounds and excipients for use in pharmaceutical formulations, such as inhalation formulations, and in the manufacture of agrochemical formulations, such as liquid-based suspensions.

It is also concerned with the production of active drug particles that are to form a dry powder formulation which is to be administered to the lung, for example using a dry powder inhaler (DPI) device. In particular, the present invention provides the characteristics and preferred processing of particles whereby the performance as such is significantly greater than conventional DPI, pressurized metered-dose inhalers (pMDIs) and nasal suspension powders, in particular DPI and pMDI powders, more particularly DPI powders. Background of the Invention

Two widely used systems for the administration of drugs to the airways are the dry powder inhalers (DPIs) comprising micronized drug particles as dry powder usually admixed with coarser excipient particles of pharmacologically inert materials such as lactose, and the pressurized metered-dose inhalers (pMDIs) which may comprise a suspension of micronized drug particles in a propellant gas. This present invention is relevant to both these methods of delivery.

Nasal delivery is a means to enable administration of drug particles to the central nervous system (CNS – nose to brain), systemic and topical nasal formulations whether as powders or of liquid suspension. Various breath activated devices deliver intranasal drugs to targeted regions of the nasal cavity, including the sinuses and the olfactory region, without lung deposition. This present invention is relevant to this method of delivery.

The control of crystal and precipitate particle size of active and other compositional ingredients is necessary in industries in which the final product form of the active ingredient of interest is in the form of a fine powder, such as in the pharmaceutical and agrochemical industries. The manner in which an active ingredient behaves in a biological system depends upon many factors inter alia the size of the particle and the crystal form. Small particles may be made by processes such as milling, but such processes may have a detrimental effect on the material properties of the milled particles. Furthermore, a significant proportion of particles may be produced which are of a shape that is unsuitable for a given end use. When particles are milled they may undergo morphological alterations, leading to undesirable surface polymorphological transformation which in turn may give rise to the formation of amorphous structures that are unsuitable for end purpose applications, such as in a pharmaceutical formulation designed for inhalation. In addition, milling generates considerable heat which may make particulate milling inappropriate, for example, where the active ingredient is a low melting solid. In addition, the physical performance of particles destined for use in aerosols may be compromised if they become highly charged as a result of milling.

Techniques for the production of drug particles may include the generation of an aerosol of droplets from a solution of the drug and subsequent spray drying of the droplets to solidify the particles. Spray drying is one of the most widely used of industrial processes involving particle formation and drying. It is highly suited for the continuous production of dry solids in either powder, granulate or agglomerate form from, for example, liquid feed stocks as solutions, emulsions or pumpable suspensions. Therefore, spray drying is an ideal process where the end-product should comply with quality standards regarding such parameters as particle size distribution, residual moisture content, bulk density, particle shape and the like. A disadvantage of conventional spray drying techniques is that the particles being dried tend to be in an amorphous form, perhaps as high as 100%, rather than in a crystalline particulate form, since solidification is typically rapid, and in addition the processing leads to a high degree of agglomeration of dried particulates. Freeze drying of aerosol droplets is also used in the art to obtain particles but again, the typically rapid solidification that occurs generally leads to the generation of amorphous particles.

WO 2004/073827 describes the preparation of particles in a process referred to as SAX, comprising the steps of forming a solution of a desired substance in a suitable solvent, generating an aerosol therefrom, collecting the aerosol droplets in a non-solvent for the said substance, and applying ultrasound to the droplets dispersed in the non- solvent to effect crystallisation of the substance. A disadvantage of this technique is the need to have a critical control over the degree of solvent evaporation from the aerosol.

Inhalation represents a very attractive, rapid and patient-friendly route for the delivery of systemically acting drugs, as well as for drugs that are designed to act locally on the lungs themselves, such as asthma, chronic obstructive pulmonary disease and infection. It is particularly desirable and advantageous to develop technologies for delivering drugs to the lungs in a predictable and reproducible manner. Drug inhalation benefits include rapid speed of onset; improved patient acceptance and compliance for a non-invasive systemic route; reduction of side effects; product life cycle extension; improved consistency of delivery; access to new forms of therapy, including higher doses, greater efficiency and accuracy of targeting.

Dry powder inhalation (DPI) plays an important role in the treatment of diseases of the lung. Primarily they were developed to overcome problems encountered using Metered Dose Inhalers (MDIs), and later, because they are propellant free and hence more environmental friendly. Using an MDI the patient has to coordinate inhalation and inhaler actuation so that the aerosol cloud can reach the lungs. Dry Powder Inhalers (DPIs) are breath actuated, so that theoretically the aerosol cloud should reach the lungs without problems. However, problems arise due to technical limitations with respect to handling, content uniformity of dose and control of dose. Also, the inspiratory flow rate varies between patients and depends on the mechanical principle of the DPI. DPIs which reduce the inspiratory flow rate considerably due to a high flow resistance are less suitable, because the rate of lung deposition of an aerosol cloud depends on the inspiratory flow rate.

Powder technology, however, for successful dry powders and DPI products remains a significant technical hurdle. Formulations must have suitable flow properties, not only to assist in the manufacture and metering of the powders, but also to provide reliable and predictable resuspension and fluidisation, and to avoid excessive retention of the powder within the dispensing device. The drug particles or particles of pharmaceutically active material (also referred to herein as API particles) in the resuspended powder must aerosolise appropriately so that they can be transported to the appropriate target area within the lung. Typically, for lung deposition, the active particles have a diameter of less than IO μm, frequently 0.1 to 7 μm or 0.1 to 5 μm.

In this kind of system the interaction between drug-to-drug and drug-to-carrier particles and particle-to-wall are of great importance for successful drug delivery to the deep lung. The interaction between particles is determined by adhesion forces such as van der Waals, capillary, and coulombic forces. The strength of these forces is affected by the particle size, shape, and morphology. Spherical or rounded particles with a rough surface are considered best for pulmonary drug delivery due to their small contact area and increased separation distance between particles. Large separation distance decreases the attachment forces and improves the powder dispersion. Particle engineering for the optimum drug particles together with DPI device engineering are essential for efficient drug delivery via the lungs. WO 2006056812 reports the invention concerned with a refinement of the processing of particles that are to form a dry powder formulation which is to be administered to the lung using a dry powder inhaler (DPI) device whereby the processing of particles of active material and particles of carrier material is carried out in the presence of additive material to provide a powder composition which exhibits excellent powder properties.

When dry powders are produced in conventional processes, the active particles will vary in size, and often this variation can be considerable. This can make it difficult to ensure that a high enough proportion of the active particles are of the appropriate size for administration to the correct site. It is therefore desirable to have a dry powder formulation wherein the size distribution of the active particles is as narrow as possible. For example, preferably the particle distribution is Gaussian, preferably the particle distribution is monomodal. Further, for example, the geometric standard deviation of the active particle aerodynamic or volumetric size distribution is preferably not more than 2, more preferably not more than 1.8, not more than 1.6, not more than 1.5, not more than 1.4, or even not more than 1.2. This will improve dose efficiency and reproducibility.

The Mass Median Aerodynamic Diameter (MMAD) is the particle diameter below which 50% of the particles enter an impactor suitable for determining in vitro performance of inhaled drug particles and takes account of both shape and density. A sample with a MMAD of (say) 5 μm will have 50 per cent of the total mass (i.e. not the total number) of particles with a diameter of more than 5 μm and 50 per cent with a diameter of less than 5 μm.

Fine particles, with an MMAD of less than 10 μm and smaller, tend to be increasingly thermodynamically unstable as their surface area to volume ratio increases, which provides an increasing surface free energy with this decreasing particle size, and consequently increases the tendency of particles to agglomerate and the strength of the agglomerate. In the inhaler, agglomeration of fine particles and adherence of such particles to the walls of the inhaler are problems that result in the fine particles leaving the inhaler as large, stable agglomerates, or being unable to leave the inhaler and remaining adhered to the interior of the inhaler, or even clogging or blocking the inhaler.

The uncertainty as to the extent of formation of stable agglomerates of the particles between each actuation of the inhaler, and also between different inhalers and different batches of particles, leads to poor dose reproducibility. Furthermore, the formation of agglomerates means that the MMAD of the active particles can be vastly increased, with agglomerates of the active particles not reaching the required part of the lung. These μm to sub μm particle sizes required for deep lung or systemic delivery lead to the problem that the respirable active particles tend to be highly cohesive, which means they generally exhibit poor flowability and poor aerosolisation.

To overcome the highly cohesive nature of such respirable active particles, formulators have, in the past, included larger carrier particles of an inert excipient in powder formulations, in order to aid both flowability and drug aerosolisation. These large carrier particles have a beneficial effect on the powder formulations because, rather than sticking to one another, the fine active particles tend to adhere to the surfaces of the larger carrier particles whilst in the inhaler device. The active particles are released from the carrier particle surfaces and become dispersed upon actuation of the dispensing device, to give a fine suspension which may be inhaled into the respiratory tract.

Whilst the addition of relatively large carrier particles does tend to improve the powder properties, it also has the effect of diluting the drug, usually to such an extent that 95% or more by total weight of the formulation is carrier. Relatively large amounts of carrier are required in order to have the desired effect on the powder properties because the majority of the fine or ultra-fine active particles need to adhere to the surfaces of the carrier particles, otherwise the cohesive nature of the active particles still dominates the powder and results in poor flowability. The surface area of the carrier particles available for the fine particles to adhere to decreases with increasing diameter of the carrier particles. However, the flow properties tend to become worse with decreasing diameter. Hence, there is a need to find a suitable balance in order to obtain a satisfactory carrier powder. An additional consideration is that one can get segregation if too few carrier particles are included, which is extremely undesirable.

An additional problem experienced by formulators is the variability in surface properties of drug and excipient particles. Each active agent powder has its own unique inherent stickiness or surface energy, which can range tremendously from compound to compound. Further, the nature of the surface energies can change for a given compound depending upon how it is processed. For example, jet milling is notorious for generating significant variations in surface properties because of the aggressive nature of the collisions it employs. Such variations can lead to increased surface energy and increased cohesiveness and adhesiveness. Even in highly regular, crystalline powders, the short range Lifshitz – van der Waals forces can lead to highly cohesive and adhesive powders.

If no carrier excipient is used, the micronized drug particles are loosely agglomerated via Lifshitz – van der Waals forces only. It is important for the function of such a formulation that no capillary forces are formed, because the particle agglomerates must be de-agglomerated in the air stream. Capillary forces are usually several times larger than, for example, Lifshitz-van der Waals forces, and the ability of such an agglomerate to be split into the single particles decreases with increasing autoadhesion forces holding the agglomerates together. Such a loose agglomeration can be achieved using a spheronisation process.

The forces acting on a particle adhered to a carrier particle when placed into an air stream can be described by lift force (the lift of smaller particle away from carrier particle; this can be neglected for micronized powders), the drag force (to compensate for adhesion and friction forces), the adhesion force and friction force (force preventing tangential displacement of two surfaces in contact). These last two hinder the detachment of the drug particles from the carrier surface. The success or failure of an interactive powder mixture as dry powder inhalation depends mainly on the magnitude of the adhesion forces, which fix the drug particles onto the carrier surface.

Obviously, a very high adhesion force is unwanted, because if the drug-carrier units cannot be split into their single components by the drag force, the whole drug- carrier units are swallowed. A balanced adhesion force promotes the split of the drug- carrier units into the micronized drug particles, which are inhaled, and the coarse carrier particles, which are swallowed. On the other hand, a too small adhesion force between drug and carrier particles might result in particle segregation and hence in higher variability in the content uniformity of dose. Also, drug particles are easier removed from the carrier particles during the sliding contact with the inhaler device walls, to which they tend to adhere firmly. Therefore, more drug is lost in the inhaler device.

The prior art teaches that the adhesion force in interactive powder mixtures for inhalation can be manipulated in several ways. First, the carrier particles can be chosen according to their median particle size, shape and surface roughness, which will result in large differences in the adhesion force for a defined mixing procedure and consequently in different aerosolisation properties.

A decrease in median particle size increases the adhesion force between drug and carrier particles. Larger adhesion forces are also found for irregular shaped or elongated carrier particles. This effect can be explained by an increase in friction during mixing. Surface roughness will either increase or decrease the adhesion force depending on the magnitude of the roughness. An increase in adhesion force will be found for extremely smooth carrier particle surfaces due to an increase in the true area of contact, or for very rough carrier particle surfaces, because here the wider spacing between the asperities allows mechanical entrapment of the micronized drug particles. In typical DPI formulation, powders are pre-blended, which results in autoadhesion between the finer and coarse carrier particles. The finer carrier particles autoadhere, mainly due to mechanical entrapment in the grooves and clefts of the coarse carrier particle surfaces. The amount of finer carrier particles is thus physically removed, and the flow properties of the carrier powder are improved. Corrasion (a geological term implying filling of valleys) leads to a less wavy carrier particle surface, so that micronized drug particles are less likely to be mechanically trapped or embedded in the carrier particle surface. Corrasion also increases the micro-roughness of the carrier particle surfaces and hence reduces the adhesion force between drug and carrier particles due to a reduced true area of contact. However, it has been found that with respect to the adhesion forces and hence the dry powder inhalation function, corrasion is not always of advantage. A minimum surface roughness of the coarse carrier particles is required to allow the embedment of the finer carrier particles in the sense of corrasion. If the coarse carrier particle surface is relatively smooth, the finer carrier particles autoadhere in such a way, that the apparent macro-roughness of the carrier particle surface is increased, which in return offers more sites for the drug particles to be mechanically trapped. In this case, the drug particles can be removed from the carrier particle surfaces only as agglomerates with the finer carrier particles during re- suspension, and the drug deposition in the lungs depends on the size of these agglomerates.

The choice of the carrier material definitely influences the strength of the adhesion forces between drug and carrier particles. However, the place of application i.e. inhalation into the lungs limits this choice dramatically. To date, only lactose monohydrate and glucose are used as carrier materials in commercial dry powder inhalations. Glucose adsorbs moisture rapidly if stored in an environment of more than 55 % relative humidity of the storage air. This will lead to strong capillary forces between drug and carrier particles. Lactose monohydrate has been claimed to reduce the vulnerability of the drug-carrier units to increased levels of humidity. However, adhesion force measurements between micronized drug and lactose monohydrate carrier particles after storage under different humidity conditions cast doubts on this opinion.

The use of an interactive powder mixture eases the handling of very low dose drugs for inhalations (for example salmeterol xinafoate: 50 microgram), so that they can be provided in single dose units such as foil blisters (such as in Advair Discus inhaler device) or capsules. Also, the increased homogeneity and reduced segregation of such mixtures is an advantage for the content. Two common techniques to produce fine particles for DPIs are mechanical micronization and spray drying. A high-energy milling operation generates particles that are highly charged and thus very cohesive. To decrease cohesiveness, surfactants are used, for example, in wet milling. The milling process also introduces surface and crystallographic damage that affects powder stability.

The produced particles often contain irregular fragments that can form strong aggregates. In addition, multistep processing may cause significant losses of materials during powder production and variability of the product properties from batch to batch. Unlike milling, the spray-drying technique is a one-step continuous process that can directly produce pharmaceutical particles with a desired size. No surfactants or other solubilizing agents are needed in the process. However, the thermal history and drying rate of each particle is difficult to control due to the high flow rates needed in the process and limited controllable parameters. Consequently, the produced particles are usually amorphous and thus sensitive to temperature and humidity variations that may cause structural changes and sintering of the particles during storage of the powder. Summary of the Invention

According to a first aspect of the invention there is provided a process for increasing the crystallinity of at least one solid material which is less than 100% crystalline, comprising contacting said solid material with solvent in which the solid material is insoluble or poorly soluble; and applying ultrasound to the solid material when in contact with said solvent.

there are provided particles comprising at least one substance obtainable by the process as described herein. There are also provided formulations having particles comprising at least one particulate substance obtainable by the process as described herein.

Such particles and formulations containing them are particularly useful in producing inhalable medicament formulations. Such particles and formulations comprising such particles exhibit surprising in vitro performance compared with conventionally prepared particles. This significant performance increase is quantified by proportional increase in Fine Particle Fraction (FPF, the % relative to the delivered dose, defined as the sum of all stages of an impinger and the throat). These particles have excellent performance characteristics for drug formulation in DPI. These particles also exhibit surprising in vivo performance compared with conventional particles, with respect to rate of dissolution and FPF delivered to the lungs. Hereinafter, a solvent in which the solid material is insoluble or poorly soluble shall be referred to as a non-solvent. As used herein, a non-solvent is one in which the solid material is soluble in an amount of less than 0.1 mg per ml at 25°C, preferably less than 0.05mg per ml at 25°C, preferably less than 0.01 mg per ml at 25°C.

Conversely, as used herein, a solvent is one in which the solid material is soluble in an amount of greater than 0.1 mg per ml at 25°C, preferably greater than 0.5mg per ml at 25°C, preferably greater than 1 mg per ml at 25°C, preferably greater than 5mg per ml at 250C, preferably greater than 10mg per ml at 25°C.

Preferably, the solid material utilised in the present invention is a particulate solid material. The particles preferably have a MMAD of up to about 10 μm, preferably from about 100 nm to about 10 μm, preferably from about 100 nm to about 5 μm and most preferably from about 100 nm to about 2 μm, for example, about 110 nm, about 250 nm, about 400nm, about 700 nm or about 1 μm, and the like.

The aerodynamic diameter is the diameter of a sphere of unit density which behaves aerodynamically as the particle of the test substance. It is used to compare particles of different sizes, shapes and densities and to predict where in the respiratory tract such particles may be deposited. The term is used in contrast to volume equivalent, optical, measured or geometric diameters which are representations of actual diameters which in themselves cannot be related to deposition within the respiratory tract.

A number of methods are available to determine the size distribution of respirable particles and (to a lesser extent) the distribution of inhalable particles; for an indication of the particle size the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) can be calculated. The MMAD is a statistically derived figure for a particle sample: for instance, an MMAD of 5 μm means that 50 % of the total sample mass will be present in particles having aerodynamic diameters less than 5 μm, and that 50 % of the total sample mass will be present in particles having an aerodynamic diameter larger than 5 μm.

Cascade impactors such as the Anderson Cascade lmpactor or Next Generation Impactor, preferably Next Generation lmpactor, can be used to obtain the size distribution of an aerosol (or a dust cloud). Air samples are withdrawn through a device, which consists of several stages on which particles are deposited on e.g. glass or glass fibre. Particles will impact on a certain stage depending on their size. The cut-off size can be calculated from the jet velocities at each stage by weighing each stage before and after sampling and the MMAD derived from these calculations. Despite the limitations in this method, namely particles bouncing off, overloading and fluctuation in flow rate etc, it is a well established technique to measure the airborne size distribution of an aerosol and it’s MMAD.

The particle size can be measured by laser diffraction techniques: Light from a laser is shone into a cloud of particles, which are suspended in a transparent gas such as air. The particles scatter the light; smaller particles scattering the light at larger angles than bigger particles. The scattered light can be measured by a series of photodetectors placed at different angles. This is known as the diffraction pattern for the sample. The diffraction pattern can be used to measure the size of the particles using well documented light scattering theory. The particles are assumed to be spherical but few particles are actually spherical. The particle diameters are calculated from the measured volume of the particle, but assume a sphere of equivalent volume.

Preferably, the solid material utilised in the present invention is obtained from a process selected from the group consisting of mechanical micron ization, milling, jet milling, grinding, rapid precipitation, freeze drying, lyophilisation, rapid expansion of supercritical solutions, spray drying or mixtures thereof. Most preferably, the solid material utilised in the present invention is obtained by a process of spray drying. Conventional spray drying techniques may be used. Preferably, the SAX process, such as that disclosed in WO 2004/073827, is not used.

Preferably, prior to the application of one of the above processes, the solid material is substantially amorphous, for example, less than 50% crystalline, more preferably less than 40% crystalline, more preferably less than 25% crystalline, more preferably less than 10% crystalline, more preferably less than 5% crystalline, for example less than 1% crystalline.

When the solid material utilised in the present invention is obtained from mechanical micron ization, milling, jet milling, grinding or mixtures thereof, the solid material prior to one of these processes may be substantially crystalline, such as more than 50% crystalline, for example more than 60% crystalline, for example more than 75% crystalline, for example more than 90% crystalline, for example more than 95% crystalline, for example more than 99% crystalline. After one of the four processes, or mixtures thereof, the solid material may be substantially crystalline at the core of the particle, and substantially amorphous on the outer layer of the particle.

A number of techniques may be used to determine crystalline content. For example, PXRD (Powder X-ray Diffraction) is a technique for looking at X-ray Diffraction patterns in solid materials. Crystalline particles have distinct ‘finger-print’ patterns for a given polymorph. Conversely amorphous compounds show little or no diagnostic patterns and show up simply as a broad hump or noise. Differential Scanning Calorimetry (DSC) also reveals a clean melting point and measurement of heat of fusion which can equate to level of crystallinity in a given sample. Amorphous materials show inconsistent behaviour in the DSC profile. DSC of crystalline materials illustrates a sharp endotherm indicating crystalline nature. Dynamic Vapor Sorption (DVS) provides a rapid and continuous method for measuring the isotherm and moisture uptake behaviour of crystalline and amorphous materials. In conjunction with DSC it can be used to measure the stability of products. Finally Raman analysis can give an indication of crystalline material and indeed distinguish between different polymorphs. Amorphous materials do not have the same diagnostic patterns and so are distinguishable from crystalline phases. For the purposes of the present application, Differential Scanning Calorimetry (DSC) is the preferred method of measurement of crystallinity. DSC experiments can be performed with a number of commercial apparatus including TA Instruments’ DSC Q2000 V24.2 build 107, the latter being the preferred instrument for measuring DCS according to the present invention. Typically an accurate amount of material is charged to the sample pan of the DSC instrument and subjected to a heating ramp of up to 100°C/min to around 275°C. The melting point endotherm and integral of the heat flow, as a measure of heat of fusion, is a qualitative and quantitative measurement respectively of crystallinity. In particular, for a given solid material, DSC provides a direct comparison of two samples thereof and clearly shows whether one is more or less crystalline than the other.

Additionally or alternatively, prior to the application of the present process, the solid material may comprise a metastable crystalline material.

For any particular material, the skilled person can readily determine whether a solid material is insoluble or poorly soluble therein. For example, High Performance Liquid Chromatography (HPLC) or Gas Liquid Chromatography (GLC) allow one to determine the level of solubilised substance in a liquid sample when it is saturated, by analysis of clear samples, making reference against solutions of known concentration. The former method is more typically used for pharmaceutical products whereas the latter is used when the material being analysed is sufficiently volatile to be vaporised at temperatures up to 30O0C which precludes most pharmaceutical products. Preferably, water is used as the non-solvent for poorly water soluble materials. For water soluble materials, preferably non-solvent hydrocarbons are used, for example, heptane. Further non-solvents for water soluble materials may include ethers (methyl tert-buty ether), alcohols (ethanol) and ketones (butanone) as appropriate. The ultrasound is preferably applied for a suitable period of time and temperature required to convert at least a portion of the amorphous material into crystalline material, or to convert a metastable material into a more stable material. For example, the process is preferably carried out for a period of greater than 0.1 ms, more preferably greater than 1ms, more preferably greater than 1 minute, for example, between 1 second and 24 hours, more preferably between 1 minute and 6 hours, more preferably between 5 minutes and 1 hour.

Preferably, the solid material used in the present invention is dry. This means that it is preferably substantially free from solvent, including non-solvents, water and organic solvents. This means that the solid material is substantially free of free water or solvent. By substantially free from solvent it is meant that the solid material contains less than 5% by weight of solvent, more preferably less than 4%, more preferably less than 3%, more preferably less than 2%, more preferably less than 1 %, more preferably less than 0.5%, more preferably less than 0.1% by weight of solvent.

Solid materials containing water of hydration, and molecular solvates can be substantially free from solvents since they contain only the prerequisite amount of water or solvent necessary for incorporation into the unit cell of the crystal. Otherwise they are essentially free of free water or solvent.

The process of the present invention finds particular utility in the processing of spray dried particles, comprising a substance selected from the group consisting of an active pharmaceutical ingredient, an active agrochemical ingredient, a pharmaceutical excipient, an agrochemical excipient and appropriate mixtures of two or more thereof. By “appropriate”, it is meant that active pharmaceutical ingredient may be combined with other active pharmaceutical ingredient and/or pharmaceutical excipient(s), but one would not normally combine a pharmaceutical active ingredient with an agrochemical excipient for example.


For any given solid material, the skilled person is capable of determining suitable solvents therefor, without burden. Some examples of solvent suitable for certain solid materials are as follows. Volatile organic solvents such as methanol, ethanol, dichloromethane, ethyl acetate, acetone, 2-propanol and non-organic solvents such as water would be typical solvents for pharmaceutically active ingredients.

Preferred excipients may include, for example, lactose and stearic acid. Lactose may be dissolved in water or ethanol/water mixture. Stearic acid may be dissolved in ethyl acetate or ethanol. The non-solvent (for example, that in process step (iv)) is preferably substantially free of free water (i.e., water not already bound to the solid material to form a hydrate or the like) when an anhydrous crystal is desired, and also free of any solvent in which the solid material is substantially soluble in. The non-solvent may be water when the solid material is substantially insoluble therein.

Whilst not an exhaustive list, some examples of solvent and non-solvent combinations are shown in Table 1.


Figure imgf000015_0001

Table 1

Other non-solvents suitable for preparing particles of the current invention include hydrofluoroalkane liquids selected from the group consisting of 1 ,1-difluoroethane, 1 ,1 ,1- trif luoroethane, 1 ,1 ,1 ,2-tetraf luoroethane, pentaf luoroethane, 1 ,1 ,1 ,3,3- pentaf luoropropane, 1 ,1 ,1 ,3,3,3-hexaf luoropropane, 1 ,1 ,1 ,2,3,3,3-heptaf luoropropane, 1 ,1 ,1 ,3,3-pentafluorobutane and 1 ,1 ,1 ,2,3,4,4,5,5,5-decafluoropentane. Use of such non-solvents can facilitate direct formulation for use in PMDI. In another embodiment less volatile fluorinated compounds such as perfluorodecalin can be used as non- solvent.

The concentration of the solid material (which is preferably a pharmaceutically acceptable substance, a pharmaceutically acceptable excipient or a mixture thereof) in the solution formed in step (i) of the process is preferably from 10mg/ml to 800mg/ml, more preferably in the range of 50mg/ml to 600mg/ml, more preferably 100mg/ml to 400mg/ml. During the process of the invention, the temperature of the non-solvent preferably lies between -1O0C and +1200C, subject to the non-solvent remaining in liquid form. Preferably, the temperature of the non-solvent preferably lies between O0C and 😯0C, more preferably 200C to 600C.

Preferably, the above process is sequential, and steps (iv) and (v) take place immediately after step (ii) (or immediately after optional step (iii) where this occurs). By “immediately after”, it is preferably meant that the spray dried particles of step (ii) (or step (iii) where it occurs) are processed in steps (iv) and (v) within 1 hour of undergoing step (ii), preferably within 30 minutes, preferably within 5 minutes, preferably within 1 minute of undergoing step (ii). Preferably, “immediately” means without any intermediate steps. Preferably, the above process is a continuous process. For example the process can be continuously fed with unprocessed material, and the processed material can be continuously or incrementally removed. Alternatively, the process may be a batch-type process wherein the process is fed batch-wise with unprocessed material, and the processed material can be removed in batches.


For formulations to reach the deep lung or the blood stream via inhalation, the active agent in the formulation must be in the form of very fine particles, for example, having a mass median aerodynamic diameter (MMAD) of less than 10 μm. It is well established that particles having an MMAD of greater than 10 μm are likely to impact on the walls of the throat and generally do not reach the lung. Particles having an MMAD in the region of 5 to 2 μm will generally be deposited in the respiratory bronchioles whereas particles having an MMAD in the range of 3 to 0.05 μm are likely to be deposited in the alveoli and to be absorbed into the bloodstream.

Ideally the active particles in a dry powder formulation should have an MMAD of not more than 10 μm, preferably not more than 5 μm, more preferably not more than 3 μm, more preferably not more than 2.5 μm, more preferably not more than 2.0 μm, more preferably not more than 1.5 μm, or preferably not more than 1.0 μm.

Of major importance is the composition of a dry powder inhalation. In a dry powder inhaler (DPI), a mixture of active particles (1-5 μm) and coarse carrier particles such as lactose (50-500 μm) may be used to obtain an effective drug particle discharge.

The spray dried particles preferably have a MMAD of up to about 10 μm, preferably from 100 nm to 10 μm, preferably from about 100 nm to about 5 μm and most preferably from 100 nm to about 2 μm, for example, about 110 nm, about 250 nm, about 400nm, about 700 nm, about 1 μm, and the like.

The final product of the process, the active particles, may also have a MMAD of up to about 10 μm, preferably from 100 nm to 10 μm, preferably from about 100 nm to about 5 μm and most preferably from 100 nm to about 2 μm, for example, about 110 nm, about 250 nm, about 400nm, about 700 nm, about 1 μm, and the like. The frequency of the ultrasound waves used in the process of the present invention is preferably in the range of from 16 kHz to 1 MHz, preferably from 10-500 kHz, more preferably from 10 – 100 kHz such as at 10, at 20, 40, 60, 80, or 100 kHz or at any frequency therebetween.

In addition to increasing the crystallinity of the solid material produced by the process of the present invention, the application of the ultrasound may also be used to reduce the amount of agglomerated particulate material. This agglomeration reduction preferably takes place at the same time as step (v) or (c) referred to above.

Depending on the kind of amorphous, partially amorphous, or metastable crystalline form of the solid material in contact with non-solvent that is subjected to ultrasonic irradiation, the particle may be transformed into a smaller and/or more stable form of itself. For example, an active ingredient may be transformed into a more stable crystalline form or, should the particle prior to ultrasonic irradiation be of a material that is present in an unstable amorphous form, it may be transformed into a more stable amorphous form. Whatever form the particle has when in contact with non-solvent, on application of ultrasonic irradiation as outlined herein, the particle properties are altered, resulting in the formation of more stable particles which may be used in a pharmaceutical or other application, such as an agrochemical application, in a more efficient manner. Preferably, the particles obtained from the process are highly crystalline and stable.

Once the ultrasonic irradiation step has been applied, the isolation of crystals from the particulate slurry may be carried out by any conventional means, such as by filtration, centrifugation, spray-drying, supercritical carbon dioxide extraction, simple evaporation, or mixtures of two or more such techniques. Typically, crystals are isolated using conventional evaporative methods.

By manipulating the spray drying conditions and ultrasonic treatment regime in the process of the present invention the inventors have now made it possible to provide crystals or amorphous bodies having predetermined characteristics. By treating a spray dried material with ultrasound for a predetermined period of time and temperature in a non-solvent, certain characteristics may be reproducibly obtained. These characteristics may include particle morphology, surface free energy, particle size distribution, desired polymorph, and in terms of isolated particles flowability, reduced electrostatic and cohesive / adhesive properties.

The solid material, preferably particulate solid material that is subject to the process of the invention is preferably an active ingredient or a desired precursor thereof, such as a drug or pro-drug or an agrochemical of interest that is able to form crystals or undergo alterations in morphology that results in a more stable form of the particle. Typically, such modified particles possess physical properties that make them more amenable for use in a desired context, such as in conventional drug delivery vehicles or indeed, in drug delivery vehicles that may be designed specifically for at least one given modified particle. As alluded to herein, there may be more than one particle of interest comprised in the initial solution prepared for conventional spray drying (or the initial solution or solid material of any of the other process techniques referred to herein), such as a mixture of two or more particles of interest. In such a context, two or more active ingredients of interest or a combination of at least one pro-drug and at least one drug, or two or more drugs, or two or more agro-chemicals, may be present in the initial solution as solutes or as the initial solid material, depending on the desired end use post ultrasonic treatment. Suitable particles that are able to crystallise under the process conditions of the invention include active ingredients or drugs which can be formed into crystalline particles by the process of the present invention such as corticosteroids, β2- agonists, anticholinergics, leukotriene antagonists, inhalable proteins or peptides, mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol; eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R)-6a,9a-difluoro-llb,21-dihydroxy-16a,17a- propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony-stimulating factor.

When more than one solid material is used, co-crystals may be formed. Co- crystals can be defined as crystalline complexes of two or more non-identical neutral molecular constituents, such as an active principal or desired precursor thereof, and a guest bound together in the crystal lattice through noncovalent interactions, preferably primarily hydrogen bonding. A guest may be another active principal or desired precursor thereof, or a co-crystal former.

The formation of pharmaceutical co-crystals involves incorporation of a given active pharmaceutical with another pharmaceutically acceptable molecule in the crystal lattice. The resulting multi-component crystalline phase will maintain the intrinsic activity of the parent active pharmaceutical while possessing a distinct physiochemical profile.

As used herein, the term “co-crystal former” denotes one or more additional molecules present in the same crystal structure as the active principal, or desired precursor thereof, which one or more additional molecules are capable of forming a supramolecular synthon with the active principal, or desired precursor thereof, by way of the intermolecular interactions characteristic of the bonding in a co-crystal.

the co-crystal former comprises one or more molecules having at least one synthon forming moiety selected from the following group: ether, thioether, alcohol, carbonyl, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulphate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulphonic acid, sulphonamide, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-containing heterocyclic ring (such as thiophene), N-containing heterocyclic ring (such as pyrrole, imidazole or pyridine), O-containing heterocyclic ring (such as furan, epoxide or peroxide) and hydroxamic acid moieties.

In further embodiments, the guest may be present, for example, in order to form the co-crystal with the active principal or desired precursor thereof. It is contemplated that one or more guests may be included in a co-crystal. Accordingly, the guest is not required to have an activity of its own, although it may have some activity that does not overly derogate from the desired activity of the active agent. A non-active guest may be a compound where no beneficial pharmacological activity has been demonstrated and which are appreciably biologically non-toxic or pharmacologically benign. In some situations, the guest may have the same activity as or an activity complementary to that of the active agent. The guest may be another active principal or desired precursor thereof. For example, some guests may facilitate the therapeutic effect of an active principal or desired precursor thereof. For pharmaceutical formulations, the guest may be any pharmaceutically acceptable molecule(s) that form a co-crystal with the active principal or desired precursor or its salt.

The guest, or co-crystal former, may be an acid and behave in both a neutral manner but with noncovalent interactions (primarily hydrogen bonding), such as in the case of oxalic acid or other suitable carboxylic acids when prepared as a co-crystal with caffeine, and as a proton-donor when in the case of forming ionic salts such as in the reaction or proton-exchange with an amine for example. Similarly benzoic acid and succinic acid behave in a neutral manner (without formal proton exchange) when forming a co-crystal with fluoxetine hydrochloride or in a proton-exchange manner to form ionic salts such as sodium benzoate or sodium succinate. These compounds may be ionic guests in their own right. Neutral guests are preferably nonionic guests. Ionic guests are compounds or complexes having ionic bonding. The guest may be an acid that forms hydrogen bonds with the chloride (or other anion). Ionic guests are compounds or complexes having ionic character, as exemplified by ionic interaction and attraction. The guest may be an acid that forms hydrogen bonds with the pharmaceutical ingredient. For example, suitable guests which are acids include (but not are not limited to): ascorbic acid, glucoheptonic acid, sebacic acid, alginic acid, cyclamic acid, ethane-1 ,2-disulfonic acid, 2-hydroxyethanesulfonic acid, 2-oxo-5 glutaric acid, naphthalene-1 ,5-disulfonic acid, nicotinic acid, pyroglutamic acid and 4- acetamidobenzoic acid. The solutes and active principles listed in the specification include the salt and/or solvates thereof. Co-crystals are described in WO2005/089375.

An example of a co-crystal of the present invention is sildenafil, or a pharmaceutically acceptable salt thereof, and acetylsalicylic acid (aspirin).

Other particles which may be made according to the invention include any drug or active ingredient that can be usefully delivered by inhalation, such as, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamime, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin; isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-a[[[6-[2-(2- pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophyliine, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be appreciated by the person skilled in the art that where appropriate medicaments comprising active ingredients or drugs may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament.

Particularly suitable medicaments for preparation with particles obtained in accordance with the process of the invention include anti-allergies, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate (e.g. as the sodium salt), salbutamol (e.g. as the free base or as the sulphate salt), salmeterol (e.g. as the xinafoate salt), terbutaline (e.g. as the sulphate salt), reproterol (e.g. as the hydrochloride salt), beclomethasone dipropionate (e.g. as the monohydrate), fluticasone propionate, (-)-4-amino-3,5- dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]- methyl]benzenemethanol glycopyrronium bromide, darotropium, aclidinium, tiotropium (eg. as bromide salt), theophyline, arofylline, zarfirlukast, monterlukast, carmoterol (eg. as the hydrochloride salt), formoterol (eg. as the fumarate salt), or indacaterol and physiologically acceptable salts and solvates thereof.

It will again be appreciated by the man skilled in the art that particles made by the process of the invention may contain a combination of two or more active ingredients as alluded to herein. Active ingredients may be selected from suitable combinations of the active ingredients mentioned hereinbefore. Thus, suitable combinations of bronchodilatory agents include ephedrine and theophylline, fenoterol and ipratropium, and isoetharine and phenylephrine.

Further suitable combinations of particles of active ingredients made according to the process of the invention include combinations of corticosteroids, such as budesonide, beclomethasone dipropionate and fluticasone propionate, with β2-agonists, such as salbutamol, terbutaline, salmeterol and formoterol and physiologically acceptable derivatives thereof, especially salts including sulphates.

Further suitable combinations of particles of active ingredients made according to the process of the invention include combinations such as Formoterol and Fluticasone; Beclomethasone and Formoterol; Formoterol and Mometasone; Indacaterol and Mometasone; lpatropium bromide and Albuterol; Salbutamol and Albuterol; Tiotropium bromide and Formoterol; Glycopyrronium bromide and Indacaterol; Formoterol and Ciclesonide; Beclomethasone / Salmeterol.

three ingredients can be combined including combinations of corticosteroid, bronchodilator (such as a beta agonist), and anticholinergic agent. One example is fluticasone / salmeterol / tiotropium bromide.

Other examples of particles obtainable by the process of the invention may include a cromone which may be sodium cromoglycate or nedocromil, or a carbohydrate, for example, heparin.

The particles made by the process of the invention may comprise an active ingredient suitable for inhalation and may be a pharmacologically active agent for systemic use. For example, such active particles may comprise peptides or polypeptides or proteins such as Deoxyribonuclease (DNase), leukotines or insulin (including pro- insulins), cyclosporin, interleukins, cytokines, anticytokines and cytokine receptors, vaccines, growth hormone, leuprolide and related analogues, intereferons, desmopressin, immunoglobulins, erythropoeitin and calcitonin.

Alternatively, the active ingredient made by the process of the invention may be suitable for oral administration. A drug for oral administration may be one of the systemic drugs mentioned above. The active ingredient may be a substance which exhibits low solubility in the digestive tract, for example, magnesium trisilicate, calcium carbonate and bismuth subnitrate. Organic compounds may include, for example, all products of combinatorial chemistry, rosiglitazone and other related glitazone drugs, hydrochlorothiazide, griseofulvin, lamivudine and other nuclease reverse transcriptase inhibitors, simvastatin and other statin drugs, benzafibrate and other fibrate drugs and loratidine, and any other physiologically tolerable salts and derivatives thereof.

Pharmaceutical excipients suitable for processing according to the present invention include, for example, carbohydrates especially monosaccharides such as fructose, glucose and galactose; non-reducing disaccharides such as sucrose, lactose and trehalose; non-reducing oligosaccharides such as raffinose and melezitose; non reducing starch derived polysaccharides products such as maitodextrins, dextrans and cyclodextrins; and non-reducing alditols such as mannitol and xylitol. Further suitable excipients include cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). Mixtures of two or more of any of the above excipients are also envisaged.

For use in medicine, the salts of the compounds of this invention refer to non toxic “pharmaceutically acceptable salts.” FDA approved pharmaceutical acceptable salt forms (International J. Pharm. 1986, 33,201 217; J. Pharm. Sci., 1977, Jan, 66 (1), p1) include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt forming acid or base.

Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N methyl D glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine.

Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.

Where the particles of active ingredient(s) prepared by the process of the present invention are agrochemically active, the active ingredient may for example be a plant growth regulator, herbicide, and/or pesticide, for example insecticide, fungicide, acaricide, nematocide, miticide, rodenticide, bactericide, molluscicide or bird repellant.

Examples of organic water-insoluble agrochemical active ingredients made according to the process of the invention include insecticides, for example selected from the group consisting of carbamates, such as methomyl, carbaryl, carbofuran, or aldicarb; organo thiophosphates such as EPN, isofenphos, isoxathion, chlorpyrifos, or chlormephos; organo phosphates such as terbufos, monocrotophos, or terachlorvinphos; perchlorinated organics such as methoxychlor; synthetic pyrethroids such as fenvalerate; nematicide carbamates, such as oxamyl herbicides, for example selected from the group consisting of triazines such as metribuzin, hexaxinone, or atrazine; sulfonylureas such as 2-chloro-N-[(4-methoxy-6-methyl-l,3,5-triazin-2- yl)aminocarbonyl]-benzenesulfonamide; uracils (pyrimidines) such as lenacil, bromacil, or terbacil; ureas such as linuron, diuron, siduron, or neburon; acetanilides such as alachlor, or metolachlor; thiocarbamates such as benthiocarb (SATURN), triallate; oxadiazol-ones such as oxadiazon; phenoxyacetic acids such as 2,4-D; diphenyl ethers such as fluazifop-butyl, acifluorfen, bifenox, or oxyfluorfen; dinitro anilines such as trifluralin; glycine phosphonates such as glyphosate salts and esters; dihalobenzonitriles such as bromoxynil, or ioxynil; fungicides, for example selected from the group consisting of nitrilo oximes such as cymoxanil (curzate); imidazoles such as benomyl, carbendazim, or thiophanate-m ethyl; triazoles such as triadimefon; sulfenamides such as captan; dithiocarbamates such as maneb, mancozeb, or thiram; chloronated aromatics such as chloroneb; dichloro anilines such as iprodione; aphicides, for example selected in the group consisting of carbamates, such as pirimicarb; miticides, for example selected from the group consisting of propynyl sulfites such as propargite; triazapentadienes such as amitraz; chlorinated aromatics such as chlorobenzilate, or tetradifan; and dinitrophenols such as binapacryl.

The organic water-insoluble agrochemical active ingredients may be comprised in the particles produced according to the present invention as a mixture of several ingredients. Especially preferred organic water-insoluble agrochemicai active ingredients are atrazine, cymoxanil, chlorothalanil, cyproconazole, and tebuconazole.

It will be appreciated that the non-solvent and the solvent should be selected as being suitable for a particular active ingredient or active precursor thereof. Corticosteroids, such as budesonide, beclomethasone dipropionate and fluticasone propionate may be dissolved in dichlormethane or methanol and ultrasonically treated in non-solvents such as heptane. β2-agonists, such as salmeterol xinafoate and formoterol fumarate, may be dissolved in methanol and ultrasonically treated in non-solvents such as acetone, ethyl acetate or heptane.

Following a conventional separation step, such as cyclonic separation, the dried particle is placed in contact with a non-solvent and then subjected to ultrasonic irradiation to form crystals, or to anneal and/or stabilise amorphous structures of a desired MMAD as hereinbefore described. The particles are subject to the operating vicinity of the ultrasonic probe if used, or of an ultrasonic energy transducer, such as a wrap-around ultrasonic energy transducer assembly, if such a configuration is employed. A suitable example of such a device is documented in WO 00/35579. The ultrasonic energy may be applied continuously or in a discontinuous manner, such as by pulsed application. Any suitable source of ultrasonic irradiation may be used. An ultrasonic probe may, for example, be inserted into a mixing vessel, such as a continuous ultrasonic flow cell, an ultrasonic emitter may be contained in the mixing vessel, or the mixing vessel may be housed in an ultrasonic bath or it may have an ultrasound transducer fixed to the external walls of the mixing vessel. The amplitude and frequency of the ultrasound waves affects the rate of nucleation and crystal growth. The frequency of the ultrasound waves may for example be from 16 kHz to 1 MHz, preferably from 10- 500 kHz, more preferably from 10 – 100 kHz such as at 10, at 20, 40, 60, 80, or 100 kHz or at any frequency therebetween, such as, 30 kHz or 50 kHz.

The ultrasonic irradiation is employed at an amplitude or power density that is appropriate for the production of crystals of the desired size, for a pre-determined application. For laboratory probe systems with an emitting face of, for example 80 cm2, the amplitude selected may be from about 1 – 30 μm, typically from 3 – 20 μm, preferably from 5 – 10 μm, for example, 6μm. Probes having a probe face surface area of 8 cm2 and a power requirement of from 5-80 W, provide a power density of from about 0.6 – 12.5 W/cm2 using an amplitude of 2-15 μm. In larger systems, preferably such as those embodied in WO 03/101577, comprising transducers bonded onto the flow cell, for example a 6 litre flow cell, the power density for the transducers employed may be from 10 – 100 W/L, preferably from 30-80 W/L, and more preferably from 50-75 W/L, for example 60 W/L or 70 W/L. The present invention is particularly suitable for industrial scale production.

The residence time of the mixed components in the ultrasonic flow cell may be preferably greater than 0.1 ms, more preferably greater than 1 ms, more preferably greater than 1 minute, for example between 1 second and 24 hours, more preferably between 1 minute and 6 hours, more preferably between 5 minutes and 1 hour.

Generated crystals may be gathered or harvested from the batch chamber by drawing off crystals using conventional means in the art, or as an aqueous suspension.

The particles produced according to the invention are substantially crystalline and show a reduced tendency of moisture adsorption which contributes to increase their physical and chemical stability. “Substantially crystalline” means the degree of crystallinity of the particles, expressed as weight % of the crystalline particle with respect to the total weight of the particle, is greater than 90%, preferably greater than 93%, even more preferably greater than 95%. Said particles also exhibit excellent dispersion properties allowing to easily obtaining homogenous formulations, in particular when the particles are formulated as dry powders for inhalation. The degree of crystallinity of the particle may be determined using Differential Scanning Calorimetry (DSC), X-ray powder diffraction or other techniques known to the skilled person such as microcalorimetry, preferably DSC.

the solid material is a corticosteroid and preferably is any corticosteroid insoluble or poorly-soluble in water according to the definition of solubility given in the European Pharmacopoeia Ed. 4th, 2002, which can be utilised by inhalation for the prevention and/or treatment of respiratory diseases. Preferably the corticosteriod has a single therapeutical dose higher than 50 μg, preferably equal to or higher than 80 μg, more preferably equal to higher than 100 μg.

Preferably, the corticosteroid is selected from the group consisting of beclomethasone dipropionate (BDP), budesonide, ciclesonide, mometasone and esters thereof, such as furoate, and fluticasone and esters thereof, such as propionate and furoate. In a preferred embodiment of the invention the corticosteroid is budesonide or fluticasone and salts or esters thereof.

Preferably the active particles of the invention have a volume diameter of less than 10 μm, more preferably at least 90 wt % of the active ingredient particles in a given composition have a diameter equal to or lower than 10 μm as determined by measuring the characteristic equivalent sphere diameter, known as volume diameter, by laser diffraction as described above, preferably using a Malvern or equivalent apparatus. The parameters taken into consideration are the volume diameters (VD) in microns of 10%, 50% and 90% of the particles expressed as d(10), d(50) and d(90), respectively, which correspond to the mass diameter assuming a size independent density for the particles.

Preferably no more than 10 wt % of said particles have a volume diameter d(10) lower than 0.8 μm, preferably no more than 50 wt % of said particles have a volume diameter d(50) lower than 2.0 μm, preferably at least 90 wt % of said particles have a volume diameter d(90) equal to or lower than 10 μm. Preferably 100 wt % of said particles have a volume diameter equal to or lower than 10 μm.

The active ingredients in the particles of the invention are substantially in a pure form. “Substantially in a pure form” means at least 95 % w/w pure, preferably at least 98 % or at least 99 % w/w. The chemical purity may be determined according to methods known to the skilled person such as high-performance liquid chromatography (HPLC).

In another aspect the present invention provides a formulation for administration by inhalation comprising the particles of the invention. The particles may be formulated into said formulation together with one or more pharmaceutically acceptable excipients, additives, diluents or carriers. For example, the formulation is provided in the form of suspension in a propellant as aerosol carrier to be administered by pressurized metered dose inhalers (pMDI).

The suspension formulation may comprise additional excipients such as surfactant, and wetting agent.

In a preferred embodiment, the formulation is provided in the form of dry inhalation powder, more preferably in the form of interactive ordered mixtures, i.e. by diluting the particles of the invention in a pharmacologically inert physiologically acceptable excipient consisting of coarser particles.

Advantageously, said powder formulation for inhalation may comprise the particles according to the invention and coarse particles of a physiologically acceptable excipient, hereinafter “carrier particles”, e.g. particles having a mass median particle diameter (MMD) higher than 50 μm and preferably the MMD comprised between 50 μm and 500 μm, more preferably between 150 and 400 μm, even more preferably between 210 and 355 μm. In another embodiment, the coarse particles have a MMD comprised between 90 and 150 μm. The MMD is the particle diameter that divides the frequency distribution in half; fifty percent of the aerosol mass has particles with a larger diameter, and fifty percent of the aerosol mass has particles with a smaller diameter.

Preferably at least 50% by weight of the carrier particles have a diameter of less than 500 μm, more preferably at least 80% by weight of the carrier particles have a diameter of less than 500 μm, more preferably at least 90% by weight of the carrier particles have a diameter of less than 500 μm, more preferably 100% by weight of the carrier particles have a diameter of less than 500 μm.

The physiologically acceptable excipient may be constituted of any amorphous or crystalline physiologically acceptable pharmacologically-inert material of animal or vegetable source or combination thereof. Preferred materials are crystalline sugars and for example monosaccharides such as glucose or arabinose, or disaccharides such as maltose, saccharose, dextrose or lactose. Polyalcohols such as mannitol, sorbitol, maltitol, lactitol may also be used. The most preferred material is α-lactose monohydrate.

Examples of commercial lactose are Capsulac™ and Pharmatose™. An example of commercial mannitol is Pearlitol™.

The formulation may be provided in the form of a suspension or a powder to be administered by breath activated nasal inhalers.

Said powder formulation may be administered by inhalation with any type of DPIs known in the art.

DPIs can be divided into two basic types: i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound; ii) multidose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre-loaded with quantities of active ingredient sufficient for multiple doses. On the basis of the required inspiratory flow rates (l/min) which in turn are strictly depending on their design and mechanical features, DPIs are divided in: i) low-resistance devices (> 90 l/min); ii) medium-resistance devices (about 60 l/min); iii) high-resistance devices (about 30 l/min).

Having regard to the pharmacological activity of the active ingredients, the particles of the invention may be indicated for the prevention and/or treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Other respiratory disorders characterized by obstruction of the peripheral airways as a result of inflammation and presence of mucus such as chronic obstructive bronchiolitis and chronic bronchitis may also benefit by their use.

For administration via inhalation, the particulate active ingredients produced according to the present process are preferably formulated with carrier particles. Said active ingredient may be present in 0.1%-90% by weight of the formulation, preferably 0.25%-50%, more preferably 1-25% by weight of the formulation. Preferably, the carrier particles may be present in an amount of 10-99.9% by weight of the formulation, more preferably 50%-99.75%, more preferably 75-99% by weight of the formulation.

In a particularly preferred embodiment, the active ingredient in the particle produced according to the present invention comprises (preferably consists essentially of) fluticasone propionate, budesonide, formoterol, salmeterol, beclomethasone or betamethosone, and mixtures and co-crystals thereof. This list also encompasses salts, hydrates and solvates of said compounds.

By scanning electron microscopy (SEM), it can be clearly observed that said active particles are significantly distinct when compared to the SEM image of the starting materials. It can also be appreciated that the particles of the invention exhibit a more uniform and regular spheroidal shape and do not appear to be as fractured and irregular as the starting materials with a smaller amount of fine particles being also present. Without being limited by the theory, said difference in the surface morphology is believed to contribute to explain the lower tendency of aggregation of the particles of invention, and hence their excellent dispersion properties.

Particles of active ingredient produced according to the present invention are preferably substantially spheroidal. This does not preclude particles with roughened surfaces. Preferably, the particles produced according to the present invention have an average ratio of their largest diameter to their smallest diameter of 1.3-1 :1 , more preferably 1.25-1 :1 , more preferably, 1.2-1.01 :1 , more preferably 1.15-1.02:1 , more preferably, 1.1-1.03:1 , more preferably, 1.075-1.05:1. Thus, it can be seen that the particles of the present invention are substantially spheroidal.

A number of particles size and shape analysis instruments are available such as the Sympatec QICPIC image analysis sensor, which combines particle size and shape analysis. This technique with extremely short exposure time of less than 1 ns allows for the use of dispersion units to provide clear images also from fastest particles with a speed of up to 100 m/s. This guarantees proper dispersion of agglomerated fine and cohesive powders. Particle sizes of between 1 μm and 20 μm can measured. The primary measurement data is stored in 30000 primary classes and can be evaluated in individually definable formats. Pre-defined set of size classes allow an easy adoption to existing measurement specifications. A high performance data compression module supports the acquisition of up to 500 images per second. Particles of less than 1 μm can be measured by laser diffraction techniques such as Malvern or Sympactec diffraction as described earlier, preferably Malvern laser diffraction.

It is well known that the force required to aerosolise an adhered API drug particle is directly proportional to the sum of the surface energies of the contiguous surfaces, and inversely proportional to the projected contact area. Thus the most common approaches to improve the aerosol isation efficiency in DPI is to reduce the surface free energy of the contacting surfaces or modify the particle shape to limit contact area. Surface area is not solely determined by particle size and shape; the surface morphology also contributes to surface area: corrugated (i.e. rough) particles have more surface area than smooth particles that occupy the same volume.

Drug particles prepared by the method of this invention can be defined by specific surface morphology. The interparticulate forces can be modulated to enhance lung deposition. Ideally, the contact area and thus the forces should be adjusted to a level that provides enough adhesion between drug and carrier to provide a stable formulation, yet allows easy separation upon inhalation. The influence of surface corrugation on the fine-particle fraction can be clarified.

Smooth-surface lactose carrier particles have been shown to increase the fine- particle fraction and dispersibility of micronized drug, while other studies showed that corrugated carrier particles increased the fine-particle fraction. These apparently contradictory results can be explained by the postulate that the surface force balance depends on several variables, not simply surface structure.

For particles described by way of example, surface area and morphology measurements reveal that surface area is highly correlated with particle interactions. Determining the powder surface area involves measuring the volume of gas adsorbed to the powder surface at a given pressure. Over the last few decades, new techniques for studying surfaces have emerged.

The surface area of the particles of the present invention was determined by the Accelerated Surface Area and Porosimetry Analyser (model ASAP 2000, Micromeritics, Norcross, GA) using nitrogen as the adsorbate gas. The powder materials (0.3 – 0.7 g) were degassed for approximately 24 h under nitrogen at 450C to remove the preadsorbed gases and vapors from the surface of the samples. The surface area was determined by the multipoint Brunauer, Emmett and Teller (BET) method using the adsorption data in the relative pressure (P/Po) range of 0.07-0.22.

Preferably the particles of this invention will have a surface area in the range 6 – 22 m2/g, preferably 9-18 m2/g, more preferably 10-13 m2/g, more preferably about 12 m2/g.

Inverse Gas Chromatography (IGC) is a gas-phase technique for characterising surface and bulk properties of solid materials. The principles of IGC are very simple, being the reverse of a conventional gas chromatographic (GC) experiment. A cylindrical column is uniformly packed with the solid material of interest, typically a powder, fibre or film and the retention time and elution peak shape are studied for a series of well- characterized nonpolar and polar gases. A pulse or constant concentration of gas is injected down the column at a fixed carrier gas flow rate, and the time taken for the pulse or concentration front to elute down the column is measured by a detector. A series of IGC measurements with different gas phase probe molecules then allows access to a wide range. IGC is used to measure surface energy as well as to study small changes in surface characteristics caused by processing.

IGC was used to measure surface energy of the particles of this invention. IGC can be carried out with two sets of conditions. At finite dilution the adsorption isotherms can be derived from peak profiles and used to calculate adsorption energy distributions. Secondly at infinite dilution amounts of solute close to the detection limit of the instrument are injected and in this case the solute-solute interactions are small and only solute-sorbent interactions influence the measured retention time. This can yield both dispersive and specific interaction between probe (gas) molecule and stationary powder. The particles of the invention are characterised by having isoenergetic distribution of surface energy as shown quite clearly in Figure 21. The surface energy is very similar and near identical at both finite and infinite dilution for particles prepared by the preferred method of this inventions, whereas typical micronized particles show dramatic variances at finite and infinite dilution.

Atomic force microscopy (AFM) can be used to measure the cohesive-adhesive balance and works by measuring height, with the probing tip placed in contact with the surface of the sample (contact mode atomic force microscopy) or very close to the surface of the sample (noncontact and tapping mode atomic force microscopy). The probing tip is attached to an elastic cantilever that is deflected proportionally to the force experienced by the tip. The atomic force microscope raster-scans the sample, producing a matrix of data points, from which quantitative height and roughness measurements can be extracted. Tapping mode atomic force microscopy effectively images crystals of various organic compounds, including drugs and the adhesional properties of carrier- particle lactose. Colloid probe microscopy (CPM) is routinely used to measure particle- particle adhesion between microcrystalline particles.

The degree of corrugation and surface morphology of samples was quantified using AFM. The surface topography and roughness measurements of particles of this invention were investigated using a Nanoscope IHa controller, a Multimode AFM and a J- type scanner (all Dl, Santa Babara, CA, USA). All AFM surface topography images were recorded in Tapping Mode operation, in which, imaging was conducted using TESP Olympus tips (Di, Cambridge, UK) at a scan rate of 1 Hz. Surface roughness measurements were analysed over a 1 μm X 1 μm area. To quantify the variations in the surface properties of the crystal surfaces, the root-mean-squared surface roughness measurement (Rq) and the mean surface roughness (R3) of the height deviations of the surface asperities were computed.

Prior to force measurements, particles for each batch of sample were attached onto standard V-shaped tipless cantilevers with pre-defined spring constants (DNP-020, Dl, CA, USA) using an epoxy resin glue (Araldite, Cambridge, UK). Three tips were prepared for each sample, and all probes were examined with an optical microscope (magnification 5Ox) to ensure the integrity of the attached particle, before allowing the thin layer of glue to dry.

The substrate was loaded on to the AFM scanner stage, which was enclosed in a custom-built environmental chamber, in which the ambient conditions were maintained at a constant temperature of 25 0C (± 1.5 0C) and relative humidity of 35 % RH (± 3 %). The interaction forces were measured by recording the deflection of the AFM cantilever as a function of the substrate displacement (z) by applying Hooke’s Law (F = -kz). Individual force curves (n = 1024) were conducted over a 10 μm x 10 μm area at a scan rate of 4 Hz and a compressive load of 40 nN. Parameters were kept constant.

The particles of the invention are characterised by having substantially corrugated surfaces as shown in Figure 22. Preferably, particles of the present invention have nanometer scale surface corrugations. Preferably the value of Rq is between 10 and 100 nm, more preferably between 20 and 90 nm. Preferably the value of R3 is between 10 and 100 nm, more preferably between 20 and 90 nm.

The cohesive-adhesive balance (CAB) approach of the AFM colloid probe technique is a development that enables direct quantification of the cohesive and adhesive nature – “the force balance” of an API within a formulation. It is a commercially available screening tool in determining the cohesive/adhesive force interactions between potential formulation components using milligrams or less of material.

The CAB approach measures the forces of interaction between API particles, mounted as colloid AFM probes, and well-defined crystalline surfaces of the API and carrier substrates. A CAB plot generated from the interaction of a number of probes allows a characteristic measurement of the cohesive nature of the API, in relation to its adhesive propensity with an excipient material to be quantified. The development of the CAB approach has overcome a number of the limitations associated with conventional AFM colloid probe methodologies, including issues regarding instrumental validation and the need to determine the true area of contact of the interacting surfaces. A CAB value of 1 indicates that the forces of particle-carrier adhesion equals the forces of particle- particle cohesion. A CAB ratio <1 indicates that, all other variables being equal, the drug is more adhesive to the carrier than cohesive with itself, and so might be expected to form a stable, ordered mixture upon blending. A CAB ratio >1 , however, indicates that the drug is more cohesive with itself than adhesive to the carrier, suggesting that upon blending a less uniform mixture might be produced, containing agglomerates of drug. Drug-carrier combinations with a higher CAB ratio, such as >1 , results in a higher fine particle fraction (FPF) upon aerosolisation, despite potential difference between the carriers in terms of size, shape, roughness and flowability. Drug-carrier combinations with a lower CAB ratio, such as, <1 result in greater cohesion of the active particle to the carrier, therefore the active particle is more likely to remain attached to the carrier. This means that in an inhaled composition, the active particle which remains attached to the carrier particle may not reach the lung and may be deposited in the throat or on the tongue. Preferably, the particles produced according to the present invention have much lower cohesiveness than particles prepared by other methods including micronization and milling. With respect to a measure of cohesiveness, since all substrates will be different with respect to their cohesive and adhesive properties, the CAB ratio is a dimensionless value which is a more useful measure for comparison. Preferably, the particles produced according to the present invention have CAB ratios with the carrier particles of 0.8-1.3, more preferably 0.9 – 1.2, more preferably, 1.0- 1.1. This is a careful balance between the cohesion of the drug with itself and the adhesion of the drug with the carrier.

The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.

The particle size distribution of the aerosol formulations according to the invention may be measured by conventional techniques, for example by using a Next Generation lmpactor (NGI) with pre-separator for example by cascade impaction or by the “Twin Impinger” analytical process. As used herein reference to the “Twin Impinger” assay means “Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A” as defined in British Pharmacopoeia 1988, pages A204- 207, Appendix XVII C. Such methods involve filling the pre-separator with HPLC mobile phase and the cups of the NGI cups were coated with 1 % v/v silicone oil in hexane to eliminate particle bounce. Typically four individual capsules of the same formulation are discharged into the NGI under prescribed conditions. Following aerosolization, the NGI apparatus is dismantled and the inhaler, capsules and each part of the NGI washed down into known volumes of HPLC mobile phase. The mass of drug deposited on each part of the NGI can then be determined by HPLC. The FPD determined represents the mass of drug collected on stages 3 – 8 of the NGI. The FPF emitted dose is also determined. The aerosolisation efficiency as determined by percentage fine particle fraction (%FPF) or respirable fraction is also assessed.

Such techniques enable the “respirable fraction” of the aerosol formulations to be calculated. As used herein reference to “respirable fraction” means the amount of active ingredient collected in the lower chamber in the NGI per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the method described above. The formulations according to the invention have been found to have a respirable fraction of 10-30 % or more by weight of the emitted dose of the medicament, preferably 14-26 %, for example about 15.9% and about 25.9% as exemplified by examples 2 and 3 (shown in figures 13 and 19). For example 1 (budesonide), example 2 (fluticasone propionate) and example 8 (fenoterol hydrobromide) there was a 53%, 50 – 60% and 30 – 50% respectively increase in FPF for the particles of the present invention compared to the prior art.

The propellants for use in the inhalable formulations including particles according to the present invention comprise any fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellents. Preferably the propellant will be a non-solvent for the medicament. Suitable propellants include conventional hydrogen-containing chlorofluorocarbons, non-chlorofluorocarbons, hydrogen-containing fluorocarbons and perfluorocarbons, and the like. In particular the propellants HFA 134a, and HFA 227 or mixtures thereof may be advantageously used.

The formulations according to the invention may be filled into canisters suitable for delivering pharmaceutical aerosol formulations. Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.

Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. SpraymiserW).

Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters.

Typically, in batches prepared for pharmaceutical use, each filled canister is check weighed, coded with a batch number and packed into a tray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channelling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or “puff1, for example in the range of 10 to 5000 microgram medicament per puff. Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1 , 2, 3 or 4 puffs each time.


Case study 1

DOI: 10.1021/op400011s

Abstract Image

With the growing problem of drug shortages worldwide, a solution could be a centralized compact pharmaceutical manufacturing platform that produces API and finished drug product. In this paper, the development of a combined crystallization, hybrid filtration-drying-dissolution apparatus to be used in such a compact platform is discussed. Experiments were conducted to evaluate each unit operation. Crystallization experiments using a conventional stirred tank and the newly designed scraped surface crystallizer demonstrated the advantages of the new design in terms of crystallization rates, yields and the ease of automation. Postcrystallization operations were operated stepwise using the custom hybrid device that delivered satisfactory results for each operation, e.g. after filtration, Fluoxetine HCl was dried in less than 20 min, with 99% yield after dissolution in the liquid excipient.

In the quest for developing a compact pharmaceutical crystallization process, a scraped surface crystallizer and a hybrid device were developed. The scraped surface crystallizer utilized the concept of an anchor impeller to create closed clearance between the crystallizer wall and impeller. This design had successfully prevented crystal encrustation on the wall, generated larger crystals (for ease of filtration), and improved draining and washing for automation. The hybrid device intensified three unit operations (filtration, drying, dissolution/suspension) into a single unit, which has greatly conserved the limited space (for the platform) while delivering the performance demanded by each unit operation. In addition, intensifying these unit operations had potentially reduced the time and material lost due to pumping, and allowed for less contact between the API and the environment and operators. Streamlining these processes would increase yield, decrease batch time, and reduce space requirement, all of which are major concerns in both large- and small-scale API processing.


“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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