MX2007005220A - Solid particulate tadalafil having a bimodal particle size distribution - Google Patents

Abstract

Provided is a solid particulate tadalafil having a bimodal particle size distribution.

Description

PARTICULATED SOLID TADALAFIL THAT HAS A BIMODAL PARTICLE SIZE DISTRIBUTION Field of the invention The field of the invention relates to particulate tadalafil. solid that has a bimodal particle size distribution.

BACKGROUND OF THE INVENTION Tadalafil is a potent and selective inhibitor of the enzyme phosphodiesterase, PDE5 specific for cyclic guanosine monophosphate (cGMP). Inhibition of PDE5 increases the amount of cGMP, which results in smooth muscle relaxation and increased blood flow. Tadalafil consequently is currently used in the treatment of male erectile dysfunction. It is reported that tadalafil in PDR is a crystalline solid that is practically insoluble in water. It is reported that the particle size of a drug poorly soluble in water is influenced by the size of the drug particle. U.S. Patent No. 6,821,975 claims a particulate form of free drug of a compound having a formula comprising particles of the compound wherein at least 90% of the particles have a particle size of less than 40 microns (40 μ).

The particle size distribution ("PSD") of a poorly water soluble drug such as tadalafil can greatly affect its bioavailability. However, when an active pharmaceutical ingredient with a relatively low particle size is obtained, the process of reducing the particle size, such as milled, adversely affects the properties of the powder. For example, a large amount of highly fine solids can be produced by milling which can adversely affect the flow properties of the powder. There is a need in the art of tadalafil with a desirable PSD, which otherwise has good properties (such as flow properties).

Extract of the invention In one embodiment, the present invention provides solid particulate tadalafil having a bimodal size distribution.

In one embodiment, the present invention provides solid particulate tadalafil having at least one of the following particle size distributions determined in volume by the laser diffraction method: a) 41μ < d (0.9) 81μ; b) 41μ < d (0, 9); c) 41μ < d (0.7) < 81μ; d) 45μ < d (0.9) < 70μ; e) 60μ < d (0.5) < 80μ; f) d (0.5) < 15μ; g) 10μ < d (0.5) < 15μ; d (0.5) < 10μ; i) 1μ < d (0, l) < 2μ In one embodiment, the present invention provides a process for preparing solid particulate tadalafil from any of the preceding embodiments comprising combining the solid particulate tadalafil having at least two different particle size distributions.

Pharmaceutical compositions and the use of them are also provided.

Brief Description of the Figures Figure 1 shows a representative particle size distribution for a solid particulate tadalafil within the scope of the invention.

Detailed description of the invention One embodiment of the present invention includes a solid particulate tadalafil having a bimodal particle size distribution. Tadalafil solid in the form of. powder or particulate granulate composed of a plurality of discrete particles, or individual units of mass, of tadalafil which is in the nominal size range of some to a few hundred microns, μ (10 ~ 6 m).

Since only a fraction of tadalafil should be reduced in size for the bimodal distribution, the final product has fewer particles that have gone through a successive reduction in particle size; These particles are fine solids that adversely affect the flow properties of a powder. Moreover, the bimodal particle size distribution generally has advantages such as good overall properties, good mixing properties and good dissolution profiles.

Frequently, it is inconvenient or impractical to compare samples of particulate tadalafil based on the total accumulated PSD (Particle Size Distribution) or its first derivative. In most cases relevant to the invention, it is possible to compare samples of solid particulate tadalafil on the basis of individual points in the cumulative distribution curve, represented as d (0, X) = Y (where X and Y are Arabic nume), each "d" describes a point individual in the cumulative PSD curve. The number "X" represents the percentage (number, volume, or weight) of, particles in the population that has a nominal size of up to and that includes "Y". That is, d (0, 9) = 41μ is the distribution such that 90% of the particles have a volume of this value or less. When 41 <; d (0, 9) < 81μ, means that 90% of the particles have a volume lower than a value in this range. For example, if that value is 60, 90% of the particles have a volume of zero to 60 μ.

In one embodiment, the invention provides tadalafil having at least one of the following PSDs (which are bimodal unless used as starting material): Al) 41μ < d (0.9) < 81μ; A2) 41μ < d (0, 9) / A3) 41μ < d (0.7) < 81μ; A4) 45μ < d (0, 9) < 70μ; Bl) 5μ < d (0.5) < 15μ; B2) 10μ < d (0.5) < 15μ; ? 3) 5μ < d (0.5) < 10μ; C) 1μ < d (0, l) < 2μ The present invention provides the following combinations of size distributions: Alone, A2 alone, A3 alone, A4 alone, A5 alone, Bl alone, B2 alone, B3 alone, C alone; combination of Al and Bl; combination of Al and B2; combination of Al and B3; combination of Al and C; combination of Al, Bl and C; combination of Al, B2 and C; combination of Al, B3 and C; combination of A2 and B2; combination of A2 and B2; combination of A2 and B3; combination of A2 and C; combination of A2, Bl and C; combination A2, B2 and C; combination of A2, B3 and C; combination of A3 and Bl; combination of A3 and B2; combination of A3 and B3; combination of A3 and C; combination of A5, Bl and C; combination of A3, B2 and C; combination of A3, B3 and C; combination of A4 and Bl; combination of A4 and B2; combination of A4 and B3; combination of A4 and C; combination of? 4, Bl and C; combination of A4, B2 and C; combination of A4, B3 and C; combination of A5 and Bl; combination of A5 and B2; combination of A5 and B3; combination of A5 and C; combination of A5, Bl and C; combination of A5, B2 and C; combination of A5, B3 and C; combination of Bl and C; combination of B2 and C; and combination of B3 and C.

Preferred bimodal PSDs include 41μ < d (0.9) < 80μ; 41μ combination < d (0.9) < 81μ and 5μ < d (0.5) < 15μ; 41μ < d (0.7) < 81μ; 41μ combination < d (0.7) 81μ, 5μ < d (0.5) < 15μ and 1μ < d (0, l) < 2μ.

In another embodiment, the present invention provides solid particulate tadalafil wherein 1μ < d (0, l) < 2μ; 5μ < d (0.5) < 10μ; and 41μ < d (0.9) < 80μ. These PSDs are bimodal. For example, when the PSD is Al, two maximums are obtained in the PSD in the zero range and a value between 41μ and 81μ. In one embodiment, a bimodal PSD is obtained by combining any of Al-C with one another, wherein the initial material is not bimodal but the final product of the combination is bimodal.

Any of the above solid particulate tadalafil with the bimodal size distribution can be made by combining a first solid particulate tadalafil solid of large particle size with a second solid particulate tadalafil of small particle size. The size of the particles can be adjusted according to the desired PSD. The combination can be by any powder combination means known in the art as long as the energy input from the combination equipment to the first and second particulate tadalafil does not produce substantial particle friction.

The small and large solid particulate tadalafil can be prepared by conventional techniques. For example, after being characterized by size in its raw state, tadalafil can be milled, for example using a pin mill under suitable conditions of rotation speed and feed rate, to bring the value of the particle size within of a desirable range. The milling efficiency can be monitored by sampling. If a first pass through the mill fails to produce the necessary particle size distribution, then one or more additional passes are made. Other methods are readily available, which include a variety of milling techniques, such as hammer mills or fluid energy mills.

In one embodiment, the solid particulate tadalafil having a bimodal PSD of 40 μ (d (0.9)> 41μ), such as 41μ < d (0.9) < 81μ and / or 45μ < d (0.9) < 70μ is prepared by combining a first solid particulate tadalafil particle of large particle size, where d (0, l) 10μ and d (0, 9) 12μ, with a second solid particulate tadalafil of small particle size, wherein at least one 98% in volume of the. particles of the second tadalafil of small particle size, have a nominal particle size of 15μ or less. In one embodiment, the small particle size is d (0.9) < 10μ and the solid particulate tadalafil of large particle size is d (0.9) = 150n and 10μ < d (0, l).

The individual particles of the solid particulate tadalafil may have a regular shape, or may have an irregular shape. In most embodiments of the invention they have an irregular shape. When particles have an irregular shape, the nominal size of a particle refers to the dimension of the so-called equivalent sphere, a concept known in the field of particle size analysis.

The particles by which the solid particulate tadalafil is composed of the invention are discrete particles which, in particular embodiments, can be more or less tightly bonded agglomerates which do not dissociate when subjected to short duration low intensity ultrasound.

The individual particles of a sample or aliquot of the solid particulate tadalafil of the invention do not have a uniform size. In contrast, a sample or aliquot of the solid particulate tadalafil of the invention is composed of particles of different sizes that can be sorted or distributed by size in a group of discrete, adjacent intervals of particle size. If the size of the intervals is sufficiently small, the set of dimensioned particles approaches a continuum of particle sizes. This collection of discrete particle size ranges together with its population is called particle size distribution (PSD).

The measurement and characterization of particle size distributions are known in the art. The particle size distribution can be represented graphically as shown in Figure 1, which illustrates the particle size distribution of a solid particulate tadalafil of the invention. Curve A is the so-called accumulated distribution. The ordinate represents the fraction (fraction of number, volume or weight, preferably the volume fraction) of particles in a population that has a nominal particle size up to the indicated size at the coordinate point on the abscissa. Curve B illustrates the first derivative of the cumulative particle size distribution and is often referred to as the "discrete distribution". The first derivative of the accumulated distribution, or the discrete distribution, presents the maximum in the points that correspond to the points of inflection in the cumulative distribution curve. As shown in Figure 1, the first derivative of the accumulated PSD of the solid particulate tadalafil of the invention has two maxima and the PSD is therefore indicated as "bimodal". A bimodal PSD is a distinctive feature of the solid particulate tadalafil of the invention.

Whether d (0, X) illustrates a percentage in number, volume or weight depends on the method used to determine the PSD. Various methods of determining the PSD and the type of percentage associated with it are known in the art. When PSD is determined by the known laser diffraction method, performed according to the method described below, d (0, X) illustrates a volume average. The skilled artisan knows that the results of PSD determination by one technique can be correlated with those of other techniques on an empirical basis by routine experimentation.

The PSD of the solid particulate tadalafil of the invention is preferably determined using the known laser diffraction method. The laser diffraction method (low angle laser light diffusion) is sensitive to the volume of a particle and provides an average particle size in volume, which is equivalent to the average particle size in weight if the density is constant. In some cases, the determination of particle size by laser diffraction employs the so-called Fraunhofer approximation, based on the projected area, which includes the assumptions that the particle size is not less than the wavelength of the efficiency of the diffusion of constant light, and the opacity of the particle. The "Mastersizer S" from Malvern Instruments equipped with a small cell dispersion unit is an example of a laser diffraction particle size analyzer useful in the determination of the PSD of the solid particulate tadalafil of the present invention. Any laser diffraction method that gives an accurate result can be used.

Samples for the measurement using the Mastersizer S can be prepared by combining the sample with media such as a silicone fluid having a viscosity at 25 ° C of 10 cst. Dow Corning 200® F-10 and Silicaid® F-10 are examples of diluents useful in the measurement of particle size. The combination of the sample and the diluent (for example, the silicone fluid) is mixed by vortex mixing for 20 seconds followed by sonication for 5 seconds. Excessive sonication should be avoided to prevent hard agglomerates from breaking.

Another embodiment of the invention provides pharmaceutical compositions containing solid particulate tadalafil having a bimodal PSD. The pharmaceutical compositions may contain the following combinations of size distributions: Al solo, A2 alone, A3 alone, A4 alone, A5 alone, Bl alone, B2 alone, C2 alone; combination of Al and Bl, combination of Al and B2, combination of Al and B3, combination of Al and C, combination of Al, Bl and C, combination of Al, B2 and C, combination of Al, B3 and C, combination of A2 and Bl, combination of A2 and B2, combination of A2 and B3, combination of A3 and C, combination of A2, Bl and C, combination of? 2, B2 and C, combination of A2, B3 and C, combination of A3 and Bl, combination of A3 and B2, combination of? 3 and B3, combination of A3 and C, combination of A3, Bl and C, combination of A3, B2 and C, combination of A3, B3 and C, combination of A4 and Bl, combination of A4 and B2, combination of A4 and B3, combination of A4 and C, combination of A4, Bl and C, combination of A4, B2 and C, combination of Á4, B3 and C, combination of A5 and Bl, combination of A5 and B2, combination of A5 and B3, combination of A5 and C, combination of A5, Bl and C, combination of A5, B2 and C, combination of A5, B3 and C, combination of Bl and C, combination of B2 and C, and combination of B3 and C. In a r implementation, at least. 10% by volume of the particles have a particle size greater than 40μ (d (0, 9)> 41μ), such as 41μ < d (0, 9) < 81μ and / or 45μ < d (0, 9) < 70μ.

The pharmaceutical compositions are prepared by combining tadalafil having a bimodal PSD with a pharmaceutically acceptable excipient. In one embodiment, the solid particulate tadalafil of large particle size, wherein d (0, 1) 10μ and d (0, 9) 120μ, is combined with a second solid particulate tadalafil of small particle size, wherein at least 90% by volume of the particles of the second tadalafil of small particle size have a nominal particle size of 15μ or less; this mixture is mixed with at least one pharmaceutically acceptable excipient. In one embodiment, the solid particulate tadalafil of small particle size is d80.9) < 10 μ and the solid particulate tadalafil of large particle size is? (0.9) = 150μ and 10μ < d (0, 1).

In addition to the active ingredient (s), the pharmaceutical compositions of the present invention contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

Diluents can be added to the formulations of the present invention. The diluents increase the volume of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier to handle for the patient and caregiver. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodexrtriña, mannitol, polymethacrylates (for example, EÜDRAGI ®), potassium chloride, cellulose powder, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted in a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (eg, carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (eg, KLUCEL®), hydroxypropyl methyl cellulose (eg, METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (for example, OLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a solid pharmaceutical composition compacted in the stomach of the patient can be increased by adding a disintegrator to the composition. Disintegrators include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg, Ac-Di-Sol®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, KOLLIDON®, POLYPLASDONE®), gum guar, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, EXPLO ®) and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve dosing precision. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

When a dosage form such as a tablet is made by compaction of a powder composition, the composition is pressurized by a punch and die. Some excipients and active ingredients have a tendency to adhere to punch and die surfaces, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito-stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc fumarate.

Flavoring agents and flavor improvers make the dosage form more palatable to the patient. Flavoring and flavoring agents common for pharmaceuticals that can be included in the composition of the present invention include maltol, vanilla, ethyl vanilla, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

The solid and liquid compositions can also be stained using any pharmaceutically acceptable dye to improve their appearance and / or facilitate the identification of the product and the unit dosage level by the patient.

In the liquid pharmaceutical compositions of the present invention, the solid particulate tadalafil and any other solid excipient are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

The liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, ketostaryl alcohol, and cetyl alcohol.

The liquid pharmaceutical compositions may also contain a better pharmaceutical agent. the viscosity to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. These agents include acacia, alginic acid bentonite, carbomer, calcium or sodium of carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert s can be added to improve flavor.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

In accordance with the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The selection of excipients and the quantities used can be determined quickly by the scientist formulator based on experience and on the consideration of the standard procedures and reference works of the field.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Dosages include suitable dosages for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. Although the most appropriate administration in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can conveniently be presented in a unit dosage form and prepared by any of the methods known in the pharmaceutical art.

The dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, chips and capsules, as well as syrups, suspensions and liquid elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a solid powder or granule composition of the invention, within a hard or soft capsule. The capsule can be made with gelatin and optionally can contain a plasticizer such as glycerin or sorbitol, and an opacifying or coloring agent.

The active ingredient and the excipients can be formulated into compositions and dosage forms according to methods known in the art.

A composition for making tablets or for filling capsules can be prepared by wet granulation. In wet granulation, some or all of the ingredients and excipients in powder form are mixed and then further mixed in the presence of a liquid, generally water, which causes the powders to clump together into granules. The granulate is screened and / or milled, dried and then sieved and / or milled to the desired particle size. With the granulate tablets can then be made or other excipients, such as a glidant and / or a lubricant, can be added prior to the manufacture of tablets.

A composition for making tablets can be prepared conventionally by dry blending. For example, the mixed composition of the active ingredients and excipients can be compacted into a piece or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into a tablet.

As an alternative for dry granulation, a blended composition can be directly compressed into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. The excipients that are particularly well suited for the manufacture of tablets by direct compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica. The correct use of these and other excipients in the manufacture of tablets by direct compression is known to those who belong to the art and have experience and expertise in the particular formulation challenge of direct compression tablet manufacture.

A capsule filler of the present invention may comprise any of the mixtures and granulates that were described with reference to the manufacture of tablets, although they do not undergo the final step of tablet manufacture. - The invention in certain embodiments is illustrated with the following examples.

EXAMPLES Particle size and PSD are measured using a Malvern "Mastersizer S" (Malvern Instruments) equipped with a small cell dispersion unit, a digital dispersion controller, and a 300 RF lens (0.05μ to 900μ) . The samples were dispersed in a 10 cst F-10 silicone fluid by vortex mixing (10 seconds) followed by sonication (5 seconds). The samples were recirculated at a recirculating speed of 3000 rpm. The output was presented in mode 3 $$ D (Fraunhofer approximation).

The particulate tadalafil of large particle size used in the examples had d (0, l) 10μ and d (0.9) 120μ and 53% of the particles had d < 45μ.

The small particle size tadalafxl used in the samples it had a maximum particle size of 15μ. Alternatively, it You can use a particulate tadalafil particle size small in which 99.96% of the particles have d < 45 μ? A.

EXAMPLE 1 Two grams of a solid particulate tadalafil having a bimodal particle size distribution according to the invention were prepared by combining 0.38 g of tadalafil of large particle size and 1.62 g of tadalafil of small particle size.

The amount of solid particulate tadalafil of large particle size (x) was calculated as follows, where d = d (0.9) = 40 47. 4 *; - = lS x = 038.gr - - The bimodal particle size of the product had: d0.5) -5-8nm t? f.9) 47-61 μ ?? EXAMPLE 2 Two grams of solid particulate tadalafil according to the invention were prepared by combining 0.42 g of tadalafil of large particle size and 1.58 g of tadalafil of small particle size. The amount of tadalafil of large particle size (x) was calculated as follows, where d = d (0.9) = 45 Z 43 * .t-198 ^ 180 43 ** = * 18 5 x-0A2gr The product had a bxmodal PSD characterized by: d (0) = 1.3-1.5 μ ?? d (ft5.}. == 5-9 pa EXAMPLE 3 Two grams of a solid particulate tadalafil having a bimodal PSD according to the invention were prepared by combining 0.54 g of tadalafil of large particle size and 1.46 g of tadalafil of small particle size. The amount of tadalafil of large particle size (x) was calculated as follows, where d (0, 9) = 60 2 33.3 * -2S? = QMgr 20 The product had a bimodal PSD characterized by: d (0.1) = 1.5-1.8 μa. 3 (0.9) -60-80? A Having described the invention with reference to particular preferred embodiments and having it illustrated with Examples, those skilled in the art can appreciate modifications of the invention described and illustrated that do not depart from the spirit and scope of the invention disclosed in the specification. The Examples are given to help understand the invention but are not desired and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. All references mentioned herein are incorporated herein in their entirety.

Claims (23)

1. A solid particulate tadalafil that has a bimodal size distribution.
2. The solid particulate tadalafil according to claim 1, having at least one of the following distributions of particle size determined in volume by a laser diffraction method: a. 41μ < d (0,) < 81μ; b. 41μ < d (0, 9); c. 41μ < d (0.7) < 81μ; d. 45μ < d (0, 9) < 70μ; and. 60μ < d (0.5) < 80μ; f. 5μ < d (0.5) < 15μ; g. 10μ < d (0.5) < 15μ; h. 5μ < d (0, 5) < 10μ; i. 1μ < d (0, l) < 2μ
3. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 9) < 81μ.
4. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 9).
5. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 7) < 81μ.
6. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 45μ < d (0, 9) < 70μ.
7. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 5μ < 15μ.
8. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 10μ < 15μ.
9. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 5μ < d (0, 5) < 10μ.
10. 10. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 1μ < d (0, 1) < 2μ.
11. 11. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 60μ < d (0.5) < 80μ.
12. 12. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 0) < 81μ and 5μ < d (0, 5) < 15μ.
13. 13. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 9) < 81μ, 5μ < d (0, 5) < 15μ and 1μ < d (0, l) < 2μ.
14. 14. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0.9) < 81μ, 5μ < d (0, 5) < 10μ and 1μ < d (0, 1) < 2μ.
15. 15. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 60μ < d (0, 9), 10μ < d (0, 5) < 15μ and 1μ < (0, 1) < 2μ.
16. 6. The solid particulate tadalafil according to claim 2, which has a particle size distribution of ß? Μ < d (0, 9) < 80μ, 5μ < d (0, 5) < 10μ and 1μ =? (0, 1) < 2μ.
17. 17. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 9) < 81μ, 10μ < d (0, 5) < 15μ and 1μ < d (0, 1) < 2μ.
18. 18. The solid particulate tadalafil according to claim 2, which has a particle size distribution of 41μ < d (0, 9) < 81μ, 5μ < d (0, 5) < 10μ and 1μ < d (0, 1) < 2μ.
19. 19. A process for preparing solid particulate tadalafil according to any of the preceding claims, comprising combining at least two samples of solid particulate tadalafil having a different particle size distribution.
20. 20. A process for preparing solid particulate tadalafil according to claim 19, wherein a first tadalafil with a PSD of d (0, 1) 10μ and d (0, 9) 120μ is combined with a second tadalafil having at least one 98 % by volume of particles with a nominal particle size of 15μ or less.
21. 21. The process according to claim 20, wherein the solid particulate tadalafil of small particle size is d (0, 9) < 10μ and the solid particulate tadalafil of large particle size is d (0, 9) = 150μ and 10μ < d (0, 1).
22. 22. A pharmaceutical composition comprising particulate-solid tadalafil according to any of claims 1-18 and a pharmaceutically acceptable excipient.
23. 23. A process for preparing a pharmaceutical composition according to claim 22, comprising combining the solid particulate tadalafil according to any of claims 1 to 28 with a pharmaceutically acceptable excipient. . The use of the solid particulate tadalafil according to any of claims 1 to 18 for the manufacture of a medicament for the treatment of sexual dysfunction. A solid particulate tadalafil having a bimodal particle size distribution is provided.