FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION OF DARUNAVIR"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION;
The present invention relates to a pharmaceutical composition comprising darunavir, a process for preparing such pharmaceutical composition, and use of the said pharmaceutical composition for the prevention, treatment and prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
BACKGROUND AND PRIOR ART:
Most of the new drugs that are under development now-a-days are intended to be used as a solid dosage form that exhibits an effective and reproducible in vivo plasma concentration after oral administration, due to many advantageous features of this oral route like greater stability, smaller bulk, accurate dosage and ease in production.
But, the fact is that, most of these new drugs are poorly water soluble, not well-absorbed after oral administration and the oral delivery of such poor water soluble drugs is frequently associated with problems of low bioavailability, high intra- and inter-subject variability, and a lack of dose proportionality. It has been estimated that almost 40% of such new drugs are poorly water-soluble.
Darunavir (TMC-1 14, UIC-94017) is chemically known as [(3R,3aS,6aR)-2,3,3a,4,5,6a-Hexahydrofuro[5,4-b]furan-3-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2 methylpropyl)amino]-3-hydroxy-l-phenylbutan-2 yl]carbamate and has the following structural formula.


Darunavir is one such drug which is very slightly soluble in aqueous solution (solubility increases with decreasing pH). Therefore, the particle size is likely to be important to the rate and possibly to the extent of absorption of darunavir.
Darunavir is a HIV-1 protease inhibitor and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
Darunavir is commercially available as tablets containing darunavir ethanolate under the trade name PREZISTA® in the United States, Europe and Canada.
Further, as per the definition of bioavailability, a drug with poor bioavailability is one which exhibits poor aqueous solubility, slow dissolution rate in biological fluids, poor stability of dissolved drug at a physiological pH, poor permeation through biomembranes and extensive presystemic metabolism. Thus, bioavailability of such poor water soluble drugs has always been a major concern for formulators in the development of a dosage form of such drugs.
The major approaches that are undertaken to overcome these bioavailability problems of such poorly water soluble drugs include the pharmaceutics approach (which involves modification of the formulation, manufacturing processes or physiochemical properties of the drug), the pharmacokinetic approach (which involves altering of pharmacokinetics of the drug by modifying its chemical structure) and the biological approach (which involves an alteration in the route of drug administration).
However, the rate of drug dissolution and drug solubility are very important factors which need to be considered while adapting or opting for the biologic approach. The pharmacokinetic approach of chemical modification has infinite number of drawbacks such as being very expensive, time consuming, repetitive of chemical studies, risk of precipitating adverse effects. Hence, the pharmaceutics approach is mostly preferred as compared to the biologic or the pharmacokinetic approach.

The pharmacokinetic approach overcomes the problems or issues associated with oral absorption and bioavailability by utilizing various technologies. One such technology is to design a prodrug with the required physico-chemical properties so as to improve its bioavailability.
Especially, for BCS class IV drugs, i.e. drugs with poor solubility and poor membrane permeability, the prodrug approach is considered as the best option to enhance the bioavailability of such drugs.
Although, the prodrug approach is the best way of improving the bioavailability, it is a complex technique or phenomenon in itself which requires extensive studies to establish the safety profile of prodrugs in humans which ultimately may result in failure. Furthermore, the potential drawback of this approach is the reduced solubility of the prodrug.
Another approach to enhance the bioavailability or poorly soluble drugs is increasing the effective surface area of such drugs as bioavailability is intrinsically related to drug particle size. Particle size reduction ultimately results in increased surface area of the drug and hence improves or enhances the dissolution properties of these poor water soluble drugs.
Particle size reduction is carried out by milling techniques such as use of jet mills, rotor stator colloid mills etc. Nowadays, particle size reduction can also be achieved by micronisation and nanosuspension. Each such mentioned technique utilizes different equipments for reduction of the particle size. For example, micronization of drugs is done by milling techniques using jet mills, rotor stator colloid mills etc. The nanosuspension technique utilizes a sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants. Nanosuspensions are produced by homogenization and wet milling process.
Various other strategies or techniques that are undertaken to address the bioavailability issues include complexation, microencapsulation, use of surfactants, lipids, permeation enhancers, salt formation, cyclodextrins, solid dispersions, self emulsifying drug delivery

system etc, however all such techniques involve use of complex methods or systems and, moreover, are expensive.
WO20) 1141921 discloses an oral pharmaceutical composition of amorphous darunavir
having a d90 particle size of about 150 µm to about 250 µm.
WO20H051978 discloses a process for preparing darunavir and darunavir ethanolate
having the d0.9 particle size less than 130 µm, the d0.5 particle size less than 30µm and the
do.i particle size less than 10 um.
WO2009013356 discloses an improved tablet formulation containing an anti-HIV agent
darunavir with a dv10 particle size value in the range of 12 to 102 microns and a dv50
particle size value in the range of 47 to 249 microns.
As discussed above, employment of various complex techniques may enable us to solve the bioavailability problems that are associated with these poor water soluble drugs, such as darunavir, but however, may not produce or result in a cost effective dosage form.
Hence, there is a need to develop a formulation of darunavir, which is cost effective. which can be produced by simple manufacturing techniques and which also exhibits better or improved bioavailability,
OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition comprising crystalline darunavir.
Another object of the present invention is to provide a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm.
Another object of the present invention is to provide a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm and having improved bioavailability.

Yet another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm.
Another object of the present invention is to provide a method for treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection which comprises administering a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500µm
Another object of the present invention is to provide a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50µm to about 500 µm use in treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500µm.
According to another aspect of the present invention there is provided a process of manufacturing a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm and one or more pharmaceutically acceptable excipients.
According to yet another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm having improved bioavailability.
According to another aspect of the present invention there is provided a method of preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises

administering pharmaceutical composition comprising crystalline darunavir having d90 particle size of about 50 µm to about 500 µm
According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline darunavir having a d90 particle size of about 50 µm to about 500 µm for use in treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
DETAILED DESCRIPTION OF THE INVENTION:
Since darunavir is very slightly soluble in aqueous solutions, therefore, formulating suitable pharmaceutical compositions of darunavir which are easy to manufacture as well as which alleviate the solubility and bioavailability problems is a challenge.
Further, it is a very well-known phenomenon that the amorphous form of a drug is always more suited than its crystalline counterpart due to higher amount energy associated, increased surface area as well as enhanced bioavailability.
The inventors of the present invention have developed a pharmaceutical composition comprising crystalline darunavir.
The present invention provides a pharmaceutical composition comprising crystalline darunavir, which exhibits improved bioavailability when compared with compositions comprising amorphous darunavir.
As discussed above, the present invention relates to a pharmaceutical composition comprising crystalline darunavir, wherein crystalline darunavir has a d90 particle size of about 50 µm to about 500 µm and which exhibits improved bioavailability.
The present invention, thus, provides crystalline darunavir wherein at least 90% of the particles, by volume, have a particle size of about 50 µm to about 500 µm. Preferably, 90% of the particles, by volume, have a particle size of about 150 to about 250 µm.

The term "Darunavir" is used in a broad sense to include not only "Darunavir" per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates (such as ethanolate, hydrate), pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The term "pharmaceutical composition" includes tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, bilayered tablets, tablet in tablet, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles and the like, however, other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-ons), liposomal formulations, injection preparations, implants, depots, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations etc may also be envisaged under the ambit of the invention.
Suitably, the pharmaceutical composition, according to the present invention are presented in a solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration.
Preferably, the pharmaceutical composition is a solid oral dosage form. More preferably, the solid dosage form is in the form of tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, tablet in tablet, bilayered tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, modified release tablets or capsules, microspheres,

multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles and the like, A tablet formulation is the preferred solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.
According to one embodiment, the present invention also relates to a pharmaceutical composition comprising crystalline darunavir and atleast one pharmaceutically acceptable carrier in a form better adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, especially the vagina and mouth.
It will be understood, however, that specific dose level and frequency of dosage according to the invention for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the severity of the particular condition, and the host undergoing therapy.
According to the preferred embodiment, the pharmaceutical composition of the present invention will be administered in daily dosages of from about 240 to 800 mg, preferably from about 240 to 600 mg.
In one aspect, the pharmaceutical composition, according to the present invention, is administered in combination with ritonavir in daily dosages of ritonavir from about 10 to 200 mg.
In another aspect, the pharmaceutical composition, according to the present invention, is administered as a multilayer tablet, preferably a bilayer tablet.

In yet another aspect, the pharmaceutical composition, according to the present invention, is administered as powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, tablet in tablet, bilayered tablet, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, modified release tablets or capsules, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates directly or the powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, sprinkles and microspheres, multiparticulates which may be filled into capsules or sachets and administered in the respective dosage form thus formulated.
Such capsules or sachets, according to the present invention may also be administered by sprinkling the formulation onto a regular meal, or administered with a liquid or semi-solid beverage, such as fruit juices, water, milk, baby formulas, soft foods, apple sauce, yogurt, and the like.
Suitable excipients are used for formulating the various dosage forms according to the present invention.
According to the present invention, pharmaceutically acceptable carriers, diluents or fillers for use in the pharmaceutical composition of the present invention may comprise one or more, but are not limited to lactose (for example, spray-dried lactose, α-lactose, β-lactose), lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitot, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and the like or mixtures thereof.

According to the present invention, glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone. magnesium aluminosilicate and/or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), and the like or mixtures thereof.
According to the present invention, suitable binders may also present in the pharmaceutical composition, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol, acacia, alginic acid, agar, calcium carragenan, cellulose derivative such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, gelatin, gum arable, guar gum, tragacanth, sodium alginate, copovidone, starches, and the like or any other pharmaceutically acceptable substances with cohesive properties, or any combination thereof.
Suitable solvents used in the processes of preparing the pharmaceutical composition of the present invention, include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran and the likeor mixtures thereof.
According to the present invention, suitable disintegrants may also be present in the pharmaceutical composition, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under

examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and the like or mixtures thereof.
Additional ingredients, such as dissolving agents/ solubilisers, buffer agents, taste masking agents, release modifying agents and the like may also be added to the pharmaceutical composition of the present invention as required. The pharmaceutical composition of the present invention may also comprise additional active agents to achieve the desired therapeutic results.
The pharmaceutical composition, according to the present invention, may also optionally be coated, i.e. seal coated, enteric coated or film coated. Preferably, the pharmaceutical composition may be seal coated and then film coated. More preferably, the pharmaceutical composition may be film coated.
According to the present invention, the seal coat comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylceiiulose, polyvinylpyrrolidone, methylceliulose, carboxymethylcellulose, hypromellose, acacia, gelatin to increase adherence and coherence of the seal coat.
The HPMC component of the seal coating, if present, may be mixed with a solvent, wherein said solvent may comprise acetone, methylene chloride, isopropyl alcohol, or any combination thereof. The seal coating may also comprise talc.
Suitable film-forming agents include, but are not limited to, cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methyicelluloses, hydroxymethyl celluloses, hydroxyethyi celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methyicelluloses, sodium carboxymethyl celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, Suitable opacifiers include, but are not limited to, titanium dioxide.
Suitable anti-adhesives include, but are not limited to, talc.

Suitable polishing agents include, but are not limited to, polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (carnauba wax, candelilla wax and white wax) and the like, or any mixtures thereof.
The pharmaceutical composition, according to the present invention, may be prepared through various techniques or processes known in the art which includes, but are not limited to direct compression, wet granulation, dry granulation, slugging or compaction ,melt granulation, melt extrusion, spray drying, solution evaporation, freeze drying, direct blending, hot melt extrusion, extrusion-spheronization and the like, or combinations thereof.
According to one aspect the present invention, there is provided a process for preparing the pharmaceutical composition, which process comprises mixing crystalline darunavir with intragranular excipients, granulating/compacting, lubricating and drying the granules. Alternatively, the dried granules are compressed into tablets or processed further to the desired dosage form.
Optionally when coated, the tablet may be coated with at least one of the coats such as, but not limited to, seal coat, enteric coat, film coat or combinations thereof. The uncoated or coated tablets may also be further filled into capsules or sachets as required.
According to a preferred embodiment, the granules as obtained above may be further mixed, sieved, sifted and /or coated and filled into capsules or sachets and are administered directly.
Such capsules or sachets, according to the present invention are administered by sprinkling the formulation onto a regular meal, or to be administered with a liquid or semi-solid beverage, such as fruit juices, water, milk, baby formulas, soft foods, apple sauce, yogurt, and the like.

The pharmaceutical composition, according to the present invention can be administered in combination with other anti-HIV compounds such as, for instance, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucieoside reverse transcriptase inhibitors (NNRTIs) or other protease inhibitors.
Some antiretrovirals and in particular, some HIV protease inhibitors such as darunavir are metabolized by cytochrome P450 leading to sub-optimal pharmacokinetic profiles, causing an undesired need for more frequent and higher doses. It is therefore desirable for darunavir to be administered in combination with an inhibitor of cytochrome P450.
Examples of inhibitors of cytochrome P450 which are also HIV protease inhibitors include for example ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir, lasinavir, palinavir, telinavir, tipranavir, mozenavir, atazanavir and pharmaceutically acceptable salts and esters thereof. More particularly, the cytochrome P450 inhibitor is selected from the group comprising ritonavir, amprenavir, nelfinavir or a pharmaceuttcally acceptable salt or ester thereof, ritonavir being especially preferred.
In one embodiment, the pharmaceutical composition, according to the present invention, in combination with other anti-HIV compounds, are administered simultaneously, separately, or sequentially.
The present invention also provides a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering the pharmaceutical composition.
The present invention also provides a pharmaceutical composition for use in treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
CLINICAL STUDIES
An Open label, randomized, two-treatment, two-period, two-sequence, single dose,
crossover study in healthy adult human subjects under fasting conditions was performed.

Test Products T1 & T2 (containing darunavir hydrate equivalent to darunavir 600 mg and corresponding to Examples 1 and 2 respectively) of Cipla Limited., India were compared with the Reference Product Prezista® 600 mg tablet (containing darunavir ethanolate equivalent to darunavir 600 mg) of Tibotec Therapeutics, USA in co-administeration with 100 mg ritonavir twice daily for 5 days.

CONCLUSION
RESULT

Test Product has significantly higher rate and extent of absorption than the Reference Product.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. Example 1

Sr. No. Ingredients Quantity (Mg/Unit)
I Dry Mix & Compaction
1 Darunavir Hydrate 649.30
2 Microcrystailine Cellulose 564.38
3 Crospovidone 24.96
II Lubrication
4 Magnesium Stearate 9.36
Total (Uncoated) 1248.00
III Film Coating
5 Opadry Orange 48.00
6 Purified Water q.s.
Total (Film Coated) 1296.00
Process:
1) Darunavir Hydrate, microcrystailine cellulose, crospovidone and magnesium stearate were sifted to produce a dry mix.
2) The dry mix so obtained in step (1) was compacted and sized to produce free flowing granules.
3) The granules obtained in step (2) were lubricated with presifted magnesium stearate and compressed to produce tablets.
4) The tablets obtained in step (3) are film coated,
Example 2

Sr. No. Ingredients Quantity (Mg/Unit)
I Dry Mix & compaction 649.30
1 Darunavir Hydrate

2 Microcrystailine Cellulose 539.42

3 Crospovidone 49.92
II Lubrication
4 Magnesium Stearate 9.36
Total (Uncoated) 1248.00
III Film Coating
5 Opadry Orange 48.00
6 Purified Water q. s.
Total (Film Coated ) 1296.00
Process:
1) Darunavir Hydrate, microcrystalline cellulose, crospovidone and magnesium stearate were sifted to produce a dry mix.
2) The dry mix so obtained in step (1) was compacted and sized to produce free flowing granules.
3) The granules obtained in step (2) were lubricated with presifted magnesium stearate and compressed to produce tablets.
4) The tablets obtained in step (3) are film coated.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

WE CLAIM:
1. A pharmaceutical composition comprising crystalline darunavir or its pharmaceutically acceptable solvates, hydrates, esters or salts thereof.
2. A pharmaceutical composition according to claim 1, comprising crystalline darunavir from about 240 to 800 mg
3. A pharmaceutical composition according to claim 1, comprising crystalline darunavir having a d90 particle size in the range of about 50 µm to 500 µm.
4. A pharmaceutical composition according to claim 1, comprising crystalline darunavir having a d90 particle size in the range of about 150 µm to about 250 µm.
5. A pharmaceutical composition according to any preceding claim further comprising one or more excipients comprising, fillers or diluents, disintegrants, binders, lubricants, glidants, or any combinations thereof.
6. A pharmaceutical composition according to any preceding claim, provided in a dosage form comprising: tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, tablet in tablet, bilayered tablets, MUPS, orally disintegrating MUPS, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, capsules, granules, effervescent granules, sprinkles, sachets or any combination thereof.
7. A pharmaceutical composition according to any preceding claim, administered in combination with ritonavir, wherein ritonavir is from about 10 to 200 mg.
8. A pharmaceutical composition according to any preceding claim, prepared by direct compression, wet granulation, dry granulation, slugging or compaction, melt granulation, melt extrusion, spray drying, solution evaporation, freeze drying, direct blending, hot melt extrusion, extrusion-spheronization.

9. A pharmaceutical composition according to any preceding claim, comprising crystalline darunavir for use in treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
10. A pharmaceutical composition substantially as herein described with reference to the examples.