WO2009005338A2

WO2009005338A2 - Solid forms ult-i, ult-2 and ult-3 of emtricitabine

Info

Publication number: WO2009005338A2
Application number: PCT/NL2008/000158
Authority: WO
Inventors: Evanthia Dova; Ida Van Der Ploeg
Original assignee: Ultimorphix Technologies B.V.
Priority date: 2007-07-05
Filing date: 2008-06-23
Publication date: 2009-01-08
Also published as: WO2009005338A3; WO2009005338A8

Abstract

The present invention provides novel crystalline forms of Emtricitabine, designated Emtricitabine form ULT-I, form ULT-2 and ULT-3, methods for the preparation of Emtricitabine form ULT-I, ULT-2 and ULT-3 and the use of Emtricitabine form ULT-I and/or ULT-2 and/or ULT-3 in pharmaceutical applications, in particular in anti-HIV medicaments. The crystalline form of Emtricitabine form ULT-I, ULT-2 and/or ULT-3 can be used in combination with other anti-HIV medicaments such as Efavirenz and Tenofovir DF.

Description

Title: Solid forms of Emtricitabine

The present invention relates to novel crystalline forms of Emtricitabine, methods for their preparation and their formulation and application in the field of medicine, in particular antiviral medicines . Emtricitabine (FTC) , with trade name Emtriva® (formerly

Coviracil) , is a nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV infection in adults. Its brutoformula is C8H10FN3O3S, and its systematic name is (-)-cis- 4-amino-5-fluoro-1- [2- (hydroxymethyl) - 1, 3-oxathiolan-5-yl] - pyrimidin-2-one, CAS number 143491-57-0. Its structural formula is:

Emtricitabine is an analogue of cytidine. The drug works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA. By interfering with this process, which is central to the replication of HIV, emtricitabine can help to lower the amount of HIV, or "viral load", in a patient's body and can indirectly increase the number of immune system cells. Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness. Emtricitabine is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.

The drug is also being evaluated as a potential treatment for chronic hepatitis B.

EP 0 526 253 (WO9303027) and US 5538975 (WO9214743) describe the synthesis of Emtricitabine. Several solid forms of Emtricitabine have been reported in

US20030060645, i.e. an amorphous, Form I, Form II, Form III and some forms of racemic mixtures: ( +/-)-cis-FTC sesquihydrate, ( +/-)-cis- FTC dehydrated. Among the anti-HIV drugs which have been developed are those which target the HIV reverse transcriptase (RT) enzyme or protease enzyme, both of which enzymes are necessary for the replication of the virus. Examples of RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) . Currently, HIV-infected patients are routinely being treated with three-drug combinations. Regimens containing (at least) three NRTIs; two NRTIs in combination with one or two protease inhibitors (PI) (s) ; or two NRTIs in combination with a NNRTI, are widely used. When two or more PIs are used in these combinations, one of the PIs is often ritonavir, given at a low sub-therapeutic dose, which acts as an effective inhibitor of the elimination of the other PI (s) in the regimen, resulting in maximal suppression of the virus and thereby reducing the emergence of resistance.

Clinical studies have shown that three-drug combinations of these anti-HIV drugs are much more effective than one drug used alone or two-drug combinations in preventing disease progression and death. Numerous studies of drug combinations with various combinations of such drugs have established that such combinations greatly reduce disease progression and deaths in people with HIV infections. The name now commonly given to combinations of anti-HIV drugs is HAART (Highly Active Anti- Retroviral Therapy) .

Polymorphs

Many pharmaceutical solids or active pharmaceuticals ingredients (API, plural APIs) can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice.

The present invention relates to the solid state physical properties of the API these properties can be influenced by controlling the conditions under which the API is obtained in solid form. Solid state physical properties affect the ease with which the material is handled during processing into a pharmaceutical product such as a tablet or capsule formulation. The physical properties impact the sort of excipients, for instance, to add to an API formulation. Furthermore, the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have therapeutic consequences. The rate of dissolution is also a consideration in liquid forms of medicine as well. The solid state form of a compound may also affect its storage conditions.

These practical physical characteristics are influenced by the particular polymorphic form of a substance. One polymorphic form may give rise to thermal behavior different from that of the amorphous material or other polymorphic forms. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state ¹³C NMR spectrometry and infrared and Raman spectrometry.

The present invention relates to novel crystalline forms of Emtricitabine . The present inventors have identified novel crystalline forms, herein depicted as ULT-I, ULT-2 and ULT-3. Surprisingly, it has been found that at least one of the forms according to the invention is more stable based on its melting point and is less prone to conversion into other solid forms than the known solid forms. This form is also anhydrous and non-solvated.

Description of the Drawings:

Figure 1 illustrates the X-Ray Powder Diffraction pattern of Emtricitabine Form ULT-I.

Figure 2A illustrates the X-Ray Powder Diffraction pattern of

Emtricitabine Form ULT-2.

Figure 2B illustrates the DSC pattern of Emtricitabine Form ULT-2

Figure 2C illustrates the TGA pattern of Emtricitabine Form ULT-2. Figure 3A illustrates the X-Ray Powder Diffraction pattern of

Emtricitabine Form ULT-3.

Figure 3B illustrates the DSC pattern of Emtricitabine Form ULT-3

Figure 3C illustrates the TGA pattern of Emtricitabine Form ULT-3. Crystalline Emtricitabine form ULT-I :

Thus, in one aspect, the present invention provides crystalline Emtricitabine herein defined as Form ULT-I, characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 3.1, 10.2, 11.2, 12.9, 14.5, 17.4, 17.9, 20.5, 21.3, 22.5, 25.0, 25.7, 26.6, 28.0 and 29.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.

In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen X-ray powder diffraction peaks are selected from the above group.

In another embodiment Form ULT-I can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities :

*For normalized intensity values: L = 0-50, M = 50-70, H = 70- 100.

In another embodiment, Form ULT-I can be characterized by an XRPD substantially according to Fig 1. In another embodiment, form ULT-I is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect, "substantially free from other amorphous, crystalline and/or polymorphic forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.

The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-I of Emtricitabine comprising the steps of dissolving Emtricitabine in 1,4-dioxane and crystallizing Emtricitabine Form ULT-I by evaporation of the solvent.

Crystalline Emtricitabine form ULT-2 : Thus, in one aspect, the present invention provides crystalline Emtricitabine herein defined as Form ULT-2, characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 6.21, 12.06, 13.14, 14.32, 16.98, 18.46, 22.06, 23.3, 24.22, 25.9, 26.94, 28.9,

31.3, 32.86, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least five, at least six or at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-2 can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities :

^:For normalized intensity values: L = 0-40, M = 40-70, H = 70-

100.

In another embodiment, Form ULT-2 can be characterized by an XRPD substantially according to Fig 2A.

In another embodiment, Form ULT-2 can be characterized by an DSC substantially according to Fig 2B.

In another embodiment, Form ULT-2 can be characterized by an TGA substantially according to Fig 2C.

In another embodiment, Form ULT-2 of the present invention can be characterized by DSC with an onset at 87.3 ⁰C and a characterizing peak at 101.6 ⁰C. From the thermal analysis, it is concluded that solid form ULT-2 is anhydrous.

In another embodiment, form ULT-2 is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect, "substantially free from other amorphous, crystalline and/or polymorphic forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.

The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-2 of Emtricitabine comprising the steps of dissolving Emtricitabine, preferably in N- methyl pyrrolidone, and crystallizing Emtricitabine Form ULT-2 by evaporation of the solvent.

The present invention further relates to a method for the preparation of the crystalline form ULT-2 of Emtricitabine comprising the steps of dissolving Emtricitabine in a solvent, preferably N- methyl pyrrolidone, and crystallizing Emtricitabine Form ULT-2 by anti-solvent addition. Preferably the anti-solvent is selected from one or more of from acetone, acetonitrile, cyclohexane, nitromethane, pentane, tert- butyl methyl ether.

Crystalline Emtricitabine form ULT-3 :

Thus, in one aspect, the present invention provides crystalline Emtricitabine herein defined as Form ULT-3, characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 6.7, 13.6, 15.6, 17.8, 18.7, 19.5, 20.1, 20.6, 22.1, 23.0, 23.7, 24.9, 25.9, 27.5, 28.1, 29.1, 30.5, 32.1, 32.7, 33.6, 36.1, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least five, at least six or at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particular preferred at least fifteen, most preferred at least sixteen X-ray powder diffraction peaks are selected from the above group. In an even more preferred embodiment, at least seventeen, more preferably at least eighteen, even more preferably at least nineteen, particular at least twenty, most preferred twenty one X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-3 can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities :

rFor normalized intensity values: L = 0-40, M = 40-70, H = 70-

100.

In another embodiment, Form ULT-3 can be characterized by an XRPD substantially according to Fig 3A.

In another embodiment, Form ULT-3 can be characterized by an DSC substantially according to Fig 3B.

In another embodiment, Form ULT-3 can be characterized by an TGA substantially according to Fig 3C.

In another embodiment, Form ULT-3 of the present invention can be characterized by DSC with an onset at 148.3°C and a characterizing peak at 154.7°C. From the thermal analysis, it is concluded that solid form ULT-3 is anhydrous. In another embodiment, form ULT-3 is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect, "substantially free from other amorphous, crystalline and/or polymorphic forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.

The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-3 of Emtricitabine comprising the steps of dissolving Emtricitabine, preferably in a solvent selected from one or more from Toluene, 2, 6-Dimethyl-4- heptanone, Methanol, Butyl benzene or Amyl ether, and crystallizing Emtricitabine Form ULT-3 by evaporation of the solvent.

The present invention further relates to a method for the preparation of the crystalline form ULT-3 of Emtricitabine by anti- solvent addition comprising the steps of dissolving Emtricitabine preferably in a solvent selected from one or more from Methanol, 1,4- Dioxane, Water, Dimethylsulfoxide, 1, 2-Ethanediol, 2,2,2- Trifluoroethanol, and crystallizing Emtricitabine Form ULT-3 by anti-solvent addition. Preferably the anti-solvent is selected from one or more of from Acetonitrile, 2-Butanone, Acetone, Tetrahydrofuran, Dichloromethane, Cyclohexane, Chloroform, Pentane, Tert-Butylmethylether, Toluene.

The present invention further relates to a method for the preparation of crystalline form ULT-3 of Emtricitabine by cooling and evaporation crystallization comprising the steps of dissolving Emtricitabine in a solvent selected from one or more from n-Butyl acetate, Cyclohexanone, N,N-dimethylformamide, tert-Butanol, Cyclopentanone, l-Methoxy-2-propanol, 1-Butanol, Acetone, 1-Heptanol, 2, 2 , 2-Trifuoroethanol, 2-methanol Tetrahydropyran, Methanol, 1,4- Dioxane, Nitromethane, 1, 2-Dimethoxyethane, Ethanol, Propionitrile, 2-Propanol, Acetonitrile, Water, and crystallization of Emtricitabine Form ULT-3 by cooling and evaporation of the solvent.

Pharmaceutical formulations comprising ULT-I, ULT-2 and/or ULT-3. The present invention further relates .to pharmaceutical formulations comprising the novel crystalline forms of Emtricitabine .

Pharmaceutical formulations of the present invention contain one or more of the crystalline forms according to the present invention, such as ULT-I, ULT-2 and/or ULT-3 as disclosed herein. The invention also provides pharmaceutical compositions comprising the crystal form according to the present invention. Pharmaceutical formulations of the present invention contains the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s) as mentioned herein before.

The pharmaceutical formulations according to the invention, may further comprise, in addition to the forms ULT-I, ULT-2 and/or ULT-3, additional pharmaceutical active ingredients, preferably Anti- HIV agents and more preferably Efavirenz and/or Tenofovir DF.

In addition to the active ingredient (s) , the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes . Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel (R) ) , micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit (R) ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into 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 (e.g. Carbopol) , carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel (R) ) , hydroxypropyl methyl cellulose (e.g. Methocel (R) ) , liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone (R) ) , pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.

Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing. Excipients that may 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 the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level .

In liquid pharmaceutical compositions of the present invention, the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

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

Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, 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, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste. Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability. According to 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. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

For infections of the eye or other external tissues, e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs .

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tweenδ 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.

Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc) . Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

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

Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art. A composition for tabletting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.

A tabletting composition may be prepared conventionally by dry- blending. For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting .

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.

Moreover, the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection. The crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Ansel et al. , Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed.

The present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof. A pharmaceutical composition of the present invention comprises the crystalline form ULT-I. The crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition. The invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compounds of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Examples Experimental conditions

X-ray Diffraction Spectrometry:

XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings . Data collection was carried out at room temperature using monochromatic CuK (alpha) radiation in the two-theta region between 1.5 ° and 41.5 °. The diffraction pattern of each well is collected in two two-theta ranges (1.5 ° < 2θ < 21.5 ° for the first frame, and 19.5 ° < 2θ < 41.5 ° for the second) with an exposure time of 120 s for each frame. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors. Typically XRPD data are collected with a variance of about 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees. This has consequences for when X-ray peaks are considered overlapping.

Thermal analysis:

Melting properties were obtained from DSC thermograms, recorded with a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland) . The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6°C; delta-H(f) = 28.45 J/g) . Samples were sealed in standard 40 microliter aluminum pans and heated in the DSC from 25°C to 300⁰C, at a heating rate of 20°C/min. Dry N₂ gas, at a flow rate of 50 ml/min, was used to purge the DSC equipment during measurement.

Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA. Monitoring of the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve. The TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 300⁰C at a heating rate of 20°C/min. Dry N₂ gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.

Examples

Evaporation crystallization

A small quantity of Emtricitabine was placed in HPLC vials. Each of the used solvents were added in small amounts to a vial containing the dry Emtricitabine at room temperature. The vials were shaken and in cases where the compound did not dissolve, the solutions were heated and maintained at 60°C for 30 min. Subsequently, the solvent was evaporated from each vial under vacuum at ambient temperature. All the resulting residues were analyzed by X-ray powder diffraction. Crash crystallization with anti-solvent addition

For each solvent, a slurry was prepared which was equilibrated at ambient temperature for at least 19 hours before filtering into a set of 1.8 ml vials. To each of these vials an anti-solvent was added, using a solvent : anti-solvent ratio of 1:1. This ratio was increased to 1 : 4 in those cases where no precipitation occurred. Precipitates were recovered by centrifugation, and the solid products were dried and measured by XRPD. In the cases that no precipitation occurred the solutions were evaporated and the residues were analysed by XRPD.

ULT-I and ULT-3

A small quantity, about 18.7 mg of Emtricitabine was placed in a HPLC vial. The solvent 1,4-dioxane was added in small amounts to the vial containing the dry Emtricitabine at room temperature to a total volume of 1000 microliter. The vial was shaken and the qualitative solubility was assessed visually. The solution was heated and maintained at 60 ⁰C for 30 minutes. Subsequently, the solvent was evaporated from the vial under vacuum at 20-25 ⁰C. The evaporation time and pressure was 22.4 hr at 20 KPa. The resulting residue was analyzed by X-ray powder diffraction and identified as emtricitabine form ULT-I. XRPD re-measurement of the same solid 12 days later showed that it had transformed to ULT-3 (i.e. from ULT-I to ULT-3) . ULT -2

Evaporation crystallization

A small quantity, about 21.9 mg of the Emtricitabine was placed in a HPLC vial. The solvent N-methyl pyrrolidone was added in small amounts to the vial containing the dry Emtricitabine at room temperature to a total volume of 50 microliter. The vial was shaken and subsequently, the solvent was evaporated from the vial under vacuum at 20-25 ⁰C. The evaporation time and pressure was 112.5 hr at

20 KPa. The resulting residue was analyzed by X-ray powder diffraction and identified as Emtricitabine form ULT-2.

Anti-solvent addition

500 μl of N-methyl pyrrolidone was added to 426 mg of the

Emtricitabine. The slurry was stirred overnight and subsequently was centrifuged. In the saturated solution 500 μl of pentane was added and the precipitated solid was separated by centrifugation and dried for 7 days at RT under pressure of 2OkPa and for 6 days under 0.IkPa.

In all cases in which form ULT-2 was formed, N-methyl pyrrolidone was the stock solvent and the anti-solvent was selected from acetone, acetonitrile, cyclohexane, nitromethane, pentane, tert- butyl methyl ether.

ULT-3

Evaporation crystallization A small quantity, about 20 to 25 mg of the Emtricitabine was placed in a HPLC vial. The solvent (Toluene, 2, 6-Dimethyl-4- heptanone, Methanol, Butyl benzene or Amyl ether) was added in small amounts to the vial containing the dry Emtricitabine at room temperature to a total volume of 50 microliter. The vial was shaken and subsequently, the solvent was evaporated from the vial under vacuum at 20-25 ⁰C. The evaporation time and pressure was 112.5 hr at 20 KPa. The resulting residue was analyzed by X-ray powder diffraction and identified as Emtricitabine form ULT-3.

Anti-solvent addition

500 μl of solvent (Methanol, 1,4-Dioxane, Water, Dimethylsulfoxide, 1, 2-Ethanediol, 2, 2, 2-Trifluoroethanol) was added to about 14 to 260 mg of the Emtricitabine . The slurry was stirred overnight and subsequently was centrifuged. In the saturated solution 500 μl of anti-solvent (Acetonitrile, 2-Butanone, Acetone, Tetrahydrofuran, Dochloromethane, Cyclohexane, Chloroform, Pentane, Tert-Butyl methylether, Toluene) was added and the precipitated solid was separated by centrifugation and dried for 7 days at RT under pressure of 2OkPa and for 6 days under 0.IkPa. The resulting residue was analyzed by X-ray powder diffraction and identified as Emtricitabine form ULT-3.

Crystallisation of emtricitabine on millilitre scale using hot filtration.

A small quantity, about 63-110 mg of the Emtricitabine was placed in a HPLC vial. The crystallisation solvent (n-Butyl acetate, Cyclohexanone, N,N-dimethylformamide, tert-Butanol, Cyclopentanone, l-Methoxy-2-propanol, 1-Butanol, Acetone, 1-Heptanol, 2,2,2- Trifuoroethanol, 2-methanol Tetrahydropyran, Methanol, 1,4-Dioxane, Nitromethane, 1, 2-Dimethoxyethane, Ethanol, Propionitrile, 2- Propanol, Acetonitrile, Water) was added in small amounts to the vial containing the dry Emtricitabine at room temperature to a total volume of 100-750 microliter. Subsequently, the solutions were heated with a rate of 20 degrees Celsius to 60⁰C for 60 min and they were filtered at this temperature. The filtrated solutions were cooled with l°C/h to a temperature of 5 or 20⁰C where they remained for 24h. Subsequently, the solvents were evaporated from the vial under 20 kPa pressure at 20-25⁰C for 150-332h. Evaporation of several samples continued under 0.IkPa pressure for another 150-40Oh. The resulting residue was analysed by X-ray powder diffraction, DSC and TGA and identified as Emtricitabine form ULT-3.

Claims

1. Crystalline Emtricitabine Form ULT-I, ULT-2 and/or ULT-3.

2. Crystalline Emtricitabine ULT-I, characterized by at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 3.1, 10.2, 11.2, 12.9, 14.5, 17.4, 17.9, 20.5, 21.3, 22.5, 25.0, 25.7, 26.6, 28.0 and 29.5 degrees two- theta +/- 0.3 degrees two-theta.

3. Crystalline Emtricitabine Form ULT-I according to claim 1, characterized by a XRPD pattern substantially as set out in Table 1 and/or Fig 1.

4. Method for the preparation of form ULT-I comprising the steps of mixing Emtricitabine with 1,4-dioxane and crystallizing Emtricitabine Form ULT-I by evaporation of the solvent.

5. Crystalline Emtricitabine ULT-2, characterized by one or more of:

- at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 6.21, 12.06, 13.14, 14.32, 16.98, 18.46, 22.06, 23.3,

24.22, 25.9, 26.94, 28.9, 31.3, 32.86, degrees two-theta +/- 0.3 degrees two-theta.;

- DSC with an onset at 87.3 ⁰C and a characterizing peak at 101.6 ⁰C.

6. Crystalline Emtricitabine Form ULT-2 according to claim 1, characterized by one or more of:

- a XRPD pattern substantially as set out in Table 2 and/or Fig

2A; - a DSC substantially as set out in Fig 2B; a TGA substantially as set out in Fig 2C.

7. Method for the preparation of Emtricitabine form ULT-I comprising the steps of mixing Emtricitabin with N-methyl pyrrolidone and crystallizing Emtricitabine Form ULT-I by evaporation of the solvent.

8. Method for the preparation of the crystalline form ULT-2 of Emtricitabine comprising the steps of dissolving

Emtricitabine in N-methyl pyrrolidone and crystallizing Emtricitabine Form ULT-2 by anti-solvent addition wherein the anti-solvent is preferably selected from one or more of from acetone, acetonitrile, cyclohexane, nitromethane, pentane, tert- butyl methyl ether.

9. Crystalline Emtricitabine ULT-3, characterized by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 6.7, 13.6, 15.6, 17.8, 18.7, 19.5, 20.1, 20.6, 22.1, 23.0, 23.7, 24.9, 25.9, 27.5, 28.1, 29.1, 30.5, 32.1, 32.7, 33.6, 36.1, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/-

0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;

DSC with an onset at 148.3 ⁰C and a characterizing peak at 154.7 ⁰C.

10. Crystalline Emtricitabine Form ULT-3 according to claim 1, characterized by one or more of: a XRPD pattern substantially as set out in Table 3 and/or Fig 3A; - a DSC substantially as set out in Fig 3B; - a TGA substantially as set out in Fig 3C.

11. Method for the preparation of form ULT-3 comprising the steps of mixing Emtricitabin with Toluene, 2, 6-Dimethyl-4-heptanone, Methanol, Butyl benzene or Amyl ether and crystallizing Emtricitabine Form ULT-3 by evaporation of the solvent.

12. Method for the preparation of the crystalline form ULT-3 of Emtricitabine comprising the steps of dissolving Emtricitabine in a solvent preferably selected from one or more of from Methanol, 1,4-Dioxane, Water, Dimethylsulfoxide, 1,2- Ethanediol, 2, 2, 2-Trifluoroethanol and crystallizing Emtricitabine Form ULT-3 by anti-solvent addition wherein the anti-solvent is preferably selected from one or more of from Acetonitrile, 2-Butanone, Acetone, Tetrahydrofuran, Dichloromethane, Cyclohexane, Chloroform, Pentane, Tert-Butyl methylether, Toluene.

13. Method for the preparation of the crystalline form ULT-3 of

Emtricitabine comprising the steps of dissolving Emtricitabine in a solvent preferably selected from one or more of from n- Butyl acetate, Cyclohexanone, N, N-dimethylformamide, tert- Butanol, Cyclopentanone, l-Methoxy-2-propanol, 1-Butanol, Acetone, 1-Heptanol, 2, 2, 2-Trifuoroethanol, 2-methanol

Tetrahydropyran, Methanol, 1,4-Dioxane, Nitromethane, 1,2- Dimethoxyethane, Ethanol, Propionitrile, 2-Propanol, Acetonitrile, Water and crystallizing Emtricitabine Form ULT-3 by cooling and/or evaporation of the solvent.

14. Pharmaceutical formulation comprising ULT-I, ULT-2 and/or ULT3.

15. Use of ULT-I, ULT-2 and/or ULT-3 as a medicament.

16. Use of ULT-I, ULT-2 and/or ULT-3 in the preparation of a medicament for the treatment of HIV.

17. Use of ULT-I and/or ULT-2 and/or ULT-3 in the treatment of HIV.

18. Use of ULT-I and/or ULT-2 and/or ULT-3 in combination with another pharmaceutical ingredient, preferably an anti HIV agent, preferably Efavirenz and/or Tenofovir DF.