MXPA00000648A - Nucleotide analog compositions - Google Patents

Abstract

The invention provides crystalline forms of adefovir dipivoxil and methods to prepare the crystals. The compositions and methods of the present invention have desirable properties for large scale synthesis of crystalline adefovir dipivoxil or for its formulation into therapeutic dosages. Invention compositions include an anhydrous crystal form of adefovir dipivoxil.

Description

COMPOSITIONS OF NUCLEOTIDE ANALOGS FIELD AND BACKGROUND OF THE INVENTION The invention relates to the nucleotide analogue 9- [2- [[bis [(pivaloyloxy) -methoxy] phosphinyljmethoxy] ethyl] adenine ("adefovir dipivoxil" or "AD") and to its use. The present invention also relates to methods for synthesizing AD. The AD is the bis-pi titre value of the related compound 9- [2 - (f or s onome t or i) e t i 1] adenine ("PMEA") which has antiviral activity in animals and in humans. The AD and the PMEA have been described, for example, in the US Patent Numbers 4,724,233 and 4,808,716, in EP 481 214, in Benzaria et al., Nucleosides and Nucleotides (1995) l_4_ (3-5): 563-565, Holy et al., Collect. Czech, Chem. Commun, (1989) 54_: 2190-2201, Holy et al., Collect. Czech, Chem. Commun, 52: 2801-2809, Rosenberg et al., Collect. Czech, Chem. Commun. (1988) 5_3, 2753-2777, Starrett et al., Antiviral Res. (1992) 1_9_: 267-273; Starrett et al., J. Med. Chem. (1994) 37: 1857-1864.

REF. : 32292 date, the AD has been provided solely as a non-crystalline or amorphous form. It has not been reported that it has been prepared as a crystalline material. Methods for crystallizing organic compounds per se are described in J.A. Landgrebe, Theory and Practice in the Organic Laboratory, 2a. edition, 1977, D.C. Heath and Co., Lexington, MA, p. 43-51; ACE. Myerson, Handbook of Industrial Crystallization, 1993, Butterworth-Heinemann, Stoneham, MA, p. 1-101).

OBJECTIVES OF THE INVENTION The invention provides one or more compositions or methods that satisfy one or more of the following objects. A principal objective of the invention is to provide compositions comprising novel forms of AD that have desirable properties for large-scale synthesis or for formulation in therapeutic dosages. Another objective is to provide AD having a good melting point, and / or flow or volumetric density properties, which facilitate the manufacture and formulation of compositions containing AD. Another objective is to provide stable forms of AD during storage. Another objective is to provide AD that can be quickly filtered and dried easily. Another objective is to provide highly purified AD having at least about 97% (w / w) purity and preferably at least about 98%. Another objective is to eliminate or minimize byproducts produced during the synthesis of AD. Another objective is to provide a method for purifying AD that avoids column chromatography which is expensive and time consuming.

BRIEF DESCRIPTION OF THE INVENTION The invention achieves its primary objectives by providing crystalline AD, in particular an anhydrous crystalline form (hereinafter "Form 1" '), a hydrated form C20H32N5O8P1 • 2H20 (hereinafter "Form 2"), a solvate form of methanol, C20H32N5O8 1 • CH30H (hereinafter "Form 3"), a salt or complex of fumaric acid, C20H32N5OTP1 • C H404 (hereinafter "Form 4"), a salt or hemisulfate complex, a salt or hydrobromide complex, a hydrochloride salt or complex, a nitrate salt or complex, a salt or mesylate complex (CH3SO3H), a salt or complex of ethyl sulfonate (C2H5SO3H), a salt or complex of beta-na The membrane is a salt or complex of (S) -sulphonic acid chloride, a salt or complex of succinic acid, and a salt or complex of maleic acid, a salt or complex of ascorbic acid and a salt or complex of nicotinic acid. The embodiments of the invention include (1) crystalline Form 1 AD that essentially has a powder X-ray diffraction spectrum ("DRX"), using Cu-Ka radiation, expressed in degrees 2? in any one or more (in any combination) of about 6.9, about 11.8, about 12.7, about 15.7, about 17.2, about 20.7, about 21.5, about 22.5, and about 23.3; (2) Form 2 crystalline AD that essentially has a DRX spectrum using Cu-Ka radiation, expressed in degrees 2? in any one or more (in any combination) of about 8.7-8.9, about 9.6, about 16.3, about 18.3, about 18.9, about 19.7, about 21.0, about 21.4, about 22.0, about 24.3, about 27.9, about 30.8, and about 32.8; (3) crystalline Form 3 AD that essentially has a DRX spectrum using Cu-Ka radiation, expressed in degrees 2? in any or more (in any combination) of about 8.1, about 8.7, about 14.1, about 16.5, about 17.0, about 19.4, about 21.1, about 22.6, about 23.4, about 24.2, about 25.4, and about 30.9; and crystalline Form 4 AD that essentially has a DRX spectrum using Cu-Ka radiation, expressed in degrees 2? in any one or more (in any combination) of about 9.8, about 15.2, about 15.7, about 18.1, about 18.3, about 21.0, about 26.3, and about 31.7. The embodiments of the invention include AD crystals having the crystal morphologies shown in any one or more of Figures 4-10. In other embodiments, the invention provides methods for producing AD crystals by allowing the crystals to be formed from a crystallization solution comprising approximately 6-45% AD and approximately 55-94% crystallization solvent, wherein the solvent of crystallization is selected from the group consisting of (1) a mixture between about 1:10 v / v and about 1: 3 v / v acetoneether di-n-but i i co, (2) a mixture between about 1: 10 v / v and about 1: 3 v / v ethyl acetate: di-n-propyl ether, (3) a mixture between about 1:10 v / v and about 10: 1 v / v of t- but anol: di-n-butyl ether, (4) a mixture between about 1:10 v / v and about 1: 3 v / v methylene chloride: ether di-n-but i i co, (5) a mixture between about 1:10 v / v and about 10: 1 v / v ether diethyl 1: ether di-n-propi 1 i co, (6) a mixture between about 1:10 v / v and about 1: 3 v / v of tetrahydro furan: et er di-n-but i i co, (7) a mixture between approximately 1:10 v / v and approximately 1: 3 v / v ethyl acetate: ether di -n-butyllic, (8) a mixture between approximately 1:10 v / v and approximately 1: 3 v / v of tet rahi dropi rano: é t er di-n-but ilico, (9) a mixture between about 1:10 v / v and about 1: 3 v / v ethyl acetate: diethyl ether, (10) ether t-but i 1-meth i 1, (11) diethyl ether, (12) ether di -n -but i 1 i co, (13) t-butanol, (14) toluene, (15) isopropyl acetate, (16) ethyl acetate, (17) a mixture consisting essentially of (A) a first crystallization solvent which consists of a first dialkyl ether of the Formula Ra-0-R2 wherein R 1 is an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, R 2 is an alkyl group having 2, 3 , 4, 5 or 6 carbon atoms or both of R1 and R2 are bonded together to form a ring of 5, 6, 7 or 8 members, with the proviso that that the dialkyl ether is not the methylethyl ether, and (B) a second crystallization solvent selected from the group consisting of (a), a second dialkyl ether of the Formula R1-0-R2, wherein the second dialkyl ether is different from the first dialkyl ether, but it is not ether me ti 1 eti 1 i co, (b) toluene, (c) tetrahydrofuran, (d) t-butanol, (e) ethyl acetate, (f) methylene chloride, (g) propyl acetate and (h) isopropanol. The embodiments of the invention include crystalline, purified AD (eg, Form 1 and / or Form 2). The embodiments of the invention also include compositions comprising crystalline AD (e.g., Form 1 and / or Form 2) and one or more compounds, such as pharmaceutical excipients or compounds present in the reaction mixtures containing the crystalline AD. The embodiments of the invention include a method for producing AD crystals, which comprises dissolving the AD in methanol and allowing the crystals to form. Another embodiment is suitable crystalline AD for pharmaceutical compositions or uses comprising, for example, one or more AD of Form 1, Form 2 or Form 3 and / or Form 4, and a pharmaceutically acceptable carrier (s). ) for the treatment of viral conditions for which the PMEA is known to be active, such as a retroviral infection (HIV, ISV, FIV) or hepatitis B virus or other hepadnavirus infections, or DNA virus infection ( human cytomegalovirus or herpesviruses, eg, HSV1 or HSV2) in humans or animals. The invention provides a method for producing crystalline Form 2 AD, which comprises forming AD crystals in the presence of water. In another embodiment, a method for preparing AD comprises contacting the PMEA with chloromethyl pivalate in N-methylpyrrole idinone (NMP, 1-methyl-2-pyrrolidinone) and a trialkylamine such as triethylamine (TEA) and recovering the AD. In a further embodiment, a PMEA composition containing less than about 2% of the salt is provided, which can be used in a method comprising contacting the PMEA containing less than about 2% of the salt. In a further embodiment, an AD product is obtained by a process comprising preparing wet granules from a mixture comprising adefovir dipivoxil of Form 1, liquid, and an acceptable excipient, and optionally drying the wet granules.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a XRD pattern of Shape 1 crystals. Figure 2 shows a thermogram obtained by differential scanning calorimetry of Shape 1 crystals. Figure 3 shows an infrared absorption spectrum by Fourier transforms, Shape crystals. 1. Figures 4-10 are portraits of a photograph showing modalities of Form 1 crystals with an increase of 100X. Figures 4-10 are copies of the photographs taken with 128% increase. Figure 11 shows an XRD pattern of Form 2 crystals. Figure 12 shows a thermogram obtained by differential scanning calorimetry of Form 2 crystals. Figure 13 shows an infrared absorption spectrum by Fourier transforms, Shape crystals. 2. Figure 14 shows a DRX pattern of Form 3 crystals. Figure 15 shows a thermogram obtained by differential scanning calorimetry of Form 3 crystals. Figure 16 shows a DRX pattern of Form 4 crystals. 17 shows a thermogram obtained by differential scanning calorimetry of Form 4 crystals. Figure 18 shows an XRD pattern of crystals of the hemisulfate salt of AD. Figure 19 shows a DRX pattern of crystals of the hydrobromide salt of AD. Figure 20 shows a pattern of DRX-nitrate salt crystals of AD. Figure 21 shows a DRX pattern of crystals of the mesylate salt of AD. Figure 22 shows an XRD pattern of crystals of the ethyl sulfonate salt of AD. Figure 23 shows a crystal XRD pattern of the β-naphthylene sulfonate salt of AD. Figure 24 shows an XRD pattern of crystals of the α-naphthylene sulfonate salt of AD. Figure 25 shows a XRD pattern of crystals of the salt (S) -canforsul fonate of AD. Figure 26 shows a DRX pattern of crystals of the succinic acid salt of AD.

DETAILED DESCRIPTION OF THE INVENTION Unless stated otherwise, temperatures are in degrees Celsius (°). Ambient temperature means approximately 18 ° to 23 °. As used herein, "alkyl" means saturated, linear, branched and cyclic hydrocarbons. "Alkyl" or "alkyl portion" as used herein, unless otherwise stated, is a hydrocarbon containing 1-, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 normal structures, secondary, tertiary or cyclical. The term alkyl of 1 to 10 carbon atoms means alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples are -CH3, -CH2CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2CH2CH2CH3, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -C (CH3) 3, -CH2CH2CH2CH2CH3, -CH (CH3) CH2CH2CH3, -CH (CH2CH3) 2, -C (CH3) 2CH2CH3, -CH (CH3) CH (CH3) 2, -CH2CH2CH (CH3) 2, -CH2CH (CH3) CH2CH3, - CH2C (CH3) 3, -CH2CH2CH2CH2CH2CH3, -CH (CH3) CH2CH2CH2CH3, -CH (CH2CH3) (CH2CH2CH3), -C (CH3) 2CH2CH2CH3, -CH (CH3) CH (CH3) CH2CH3, -CH (CH3) CH2CH ( CH3) 2, -C (CH3) (CH2CH3) 2, -CH (CH2CH3) CH (CH3) 2, -C (CH3) 2CH (CH3) 2, -CH (CH3) C (CH3) 3, cyclopropyl, cyclobutyl , cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-ciclopropi -et 1- 1 i i, 2-cyclopropyl-1-ethyl, ciciohexilo, cyclopentylmethyl, 1-yl- 1 cyclobut ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl -l-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl, 2-cyclopropyl-2-propyl and 1-cyclopropyl 1-2-propyl. "Alkoxide" as used herein, unless otherwise stated, is a hydrocarbon containing 1, 2, 3, 4, 5 or 6 carbon atoms, as defined herein for alkyl, linto an oxygen atom. Examples are -0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH (CH3) 2, -OCH2CH2CH2CH3, -OCH2CH (CH3) 2, -OCH (CH3) CH2CH3, -0C (CH3) 3, -OCH2CH2CH2CH2CH3, -OCH (CH3) CH2CH2CH3, -OCH (CH2CH3) 2, -OC (CH3) 2CH2CH3, -OCH (CH3) CH (CH3) 2, -OCH2CH2CH (CH3) 2 / -OCH2CH (CH3) CH2CH3, -OCH2C (CH3) 3, -0CH (CH3 ) (CH2) 3CH3, -OC (CH3) 2 (CH2) 2CH3, -OCH (C2H5) (CH2) 2CH3, -O (CH2) 3CH (CH3) 2, -OCH2) 2C (CH3) 3, -0CH2CH (CH3) (CH2) 2CH3, and -OCH2CH2CH2CH2CH2CH3. "Trialkylamine" means a nitrogen atom substituted with three alkyl portions of 1 to 6 carbon atoms, which are independently selected. Examples are nitrogen substituted with 1, 2 or 3 portions -CH3, -CH2CH3, -CH2CH2CH3, -CH (CH3), -CH2CH2CH2CH3, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -C (CH3) 3 , -CH2CH2CH2CH2CH3, -CH (CH3) CH2CH2CH3, - CH (CH2CH3) 2, - C (CH3) CH2CH3, -CH (CH3) CH (CH3) 2, -CH2CH2CH (CH3) z, -CH2CH (CH3) CH2CH3, -CH2C (CH3) 3, -CH2CH2CH2CH2CH2CH3, -CH (CH3) CH2CH2CH2CH3, -CH (CH2CH3) (CH2CH2CH3), -C (CH3) 2CH2CH2CH3, -CH (CH3) CH (CH3) CH2CH3, -CH (CH3) CH2CH (CH3) 2, -C (CH3) (CH2CH3) 2, -CH (CH2CH3) CH (CH3) 2 / -C (CH3) 2CH (CH3) 2 / -CH (CH3) C (CH3) 3. "Heteroaryl" as used herein, includes, by way of example and not limitation, the heterocycles described in Paquette, Leo A .; Principies of Modern Heterocyclic Chemi stry (W.A. Benjamin, New York, 1968), particularly in Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A series Monographs (John Wiley &Sons, New York, 1950 to date), and particularly in Volumes 13, 14, 16, 19, and 28; and J. Am. Ch em. S or c. , (1960) 82: 5566. Examples of heterocycles include, by way of example and not limitation, pyridyl, thiazolyl, tet rahydro thiophene or triethylammonium oxidized with pyrimidinyl sulfur, furanyl, thienyl, pyrrolyl pyrazolyl, imidazolyl, tetrazolyl benzo furan , t ianaft aleni lo, indolyl indolenyl, quinolinyl, isoquinolinyl benz imidazole, piperidinyl, -piper idoni lo pyrrolidinyl, 2-pyrrolidone 1, pyrrolinyl tetrahydro furanyl, trahydroquinol inyl tet rahydro and soquinol inyl, cahidroqui nol inilo oc t ahi droi soquinol ini lo, azocinilo, triazinilo 6H-l, 2,5-thiadiazinilo, 2H, 6H-l, 5,2-ditiazinilo thienilo, thiantrenilo, pirani lo i sobenzo furani lo, cromenilo, xantenilo fenoxat ini lo , 2H-p irro 1 i lo, isothiazolyl isoxazolyl, pyrazinyl, indole isoindolyl indole, 3H-indolyl, 1H-indazole ilo purinyl, 4H-quinine in 1 lo, phthalazinyl napht iin idinyl, quinoxalinyl, quinazole inyl cinolinyl, pteridinyl, 4aH-carbazolyl carbazole ilo, b- carbol ini lo, fenantridinil, acridinil, pi rimi dini lo, phenanthrolinil, phenazyl, phenothiazinyl, furazinyl, fenoxa z ini lo, i socromani lo, chromani lo, imida zol idini 1, imida zol ini lo, pyrazolidinyl , pyrazolinyl, piperazinyl, indolinyl, and soindol inyl, quinucl idini lo, morpholinyl, oxazolidinyl, benzo tria zo 1 i 1, benz i soxa zol i 1, oxindolyl, benzoxazol ini 1, and isatinoyl. By way of example and without limitation, the heterocycles linked by carbon are linked at the 2, 3, 4, 5, or 6 position of a pyridine, the 3, 4, 5, or 6 position of a pyridazine, the 2-position, 4, 5, or 6 of a pyrimidine, the 2, 3, 5, or 6 position of a pyrazine, the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or atropropyrrole, the position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isozaxol, pyrazole or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine , position 2, 3, 4, 5, 6, 7, or 8 of a quinoline, or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. More typically, heterocycles bonded to carbon include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridinium lo, 4-pyridinyl, 5-pyridyl, pi r ida z ini lo, 6-pyridazinyl, 2-pi r imi dini 1 o, 4-pi r imi dini 1, 5-pyrimidinyl, 6-pi imi dini lo, 2 -pi razi ini lo, 3- pyrazinyl, 5-pyrazole, 6-pi radical, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and without limitation, the nitrogen-linked heterocycles are linked in the 1-position of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imi 1 ina, pyrazole, pyrazoline, 2-pi ra zol ina, 3-pi ra zo 1 ina, piperidine, piperazine, indole, indoline, lH-indazole, the 2-position of an isoindol, or isoindoline, the 4-position of a morpholine , and position 9 of a carbazole, or ß-carboline. More typically, nitrogen-linked heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pirazole, and 1-piperidinyl. As used herein, AD as a "crystalline material", "crystalline" or "crystal" means a solid AD having a substantially ordered arrangement of all constituent molecules, in a defined three-dimensional spatial network or pattern. The crystalline AD or in the form of crystals may comprise one or more of a type of composition, for example, AD * fumaric acid or AD «2H20. A crystalline material or crystal may be present in one or more crystalline dominant forms, for example, tablets, bars, plates or needles. Unless otherwise specified, explicitly or by context, the percentages are expressed as% by weight (w / w) • In this way, a solution containing at least approximately 40% AD is a solution containing at least about 40% w / w of AD. Solid AD containing 0.1% water, means that 0.1% w / w of water is associated with the solid. Crystal AD substantially free of non-crystalline AD means a solid composition in which more than about 60% of the AD is present in the composition as a crystalline material. Such compositions typically contain at least about 80%, usually at least about 90%, of one or more crystalline forms of AD, and the remainder of the AD is present as non-crystalline AD. The compositions of the invention optionally comprise salts of the compounds herein, including pharmaceutically acceptable salts comprising, for example, an uncharged portion or a monovalent anion. Salt (s) includes (n) those derived by the combination of appropriate anions such as inorganic or organic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably low toxicity acids. For example, salts of the invention can be formed from the addition of certain organic and inorganic acids, for example, HF, HCl, HBr, Hl, H2S0, H3P0, or from organic sulfonic acids, organic carboxylic acids, to basic, typically amines. Exemplary organic sulfonic acids include the sulfuric acids of ß to 16 carbon atoms, het eroar i sulphonic acids of 6 to 16 carbon atoms and alkylsulphonic acids of 1 to 16 carbon atoms such as phenyl, α-naphthyl, β-naphthyl, (S) -canfor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexi 1 sulphonic. Exemplary organic carboxylic acids include the carboxylic acids 1 to 16 carbon atoms and 1 to 1 carbon atoms of 6 to 16 carbon atoms and the heteroarcarboxy acids to 4 to 16 carbon atoms. such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hy drox imal ei co, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-f enox iben zo i co. The salts also include the salts of the compound of the invention with one or more amino acids. Many amino acids are suitable, especially amino acids that are found in nature as protein components, although the amino acid is typically one that contains a side chain with a basic or acid group, for example, lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. The salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used with synthetic intermediates of the compounds of the invention. The salts of AD are typically crystalline, such as Form 4 described herein. Modalities include compositions that occur transiently when a step or operation of the method is performed. For example, when a sodium alkoxide is contacted with a solution of 9- (2-hydroxyethyl) adenine, the composition at the start of mixing will contain negligible amounts of the sodium alkoxide. This composition will generally be present as an inhomogeneous mixture before agitation sufficient to mix the solution. That composition usually comprises negligible reaction products and comprises the majority of the reactants. In a similar way, as reaction procedures, the proportions of the reactants, products and byproducts, will change with respect to each other. These transient compositions are intermediate compounds that arise when a process step is performed and are expressly included as embodiments of the invention. The invention includes compositions comprising mixtures of two or more different types or forms of crystals, for example, Form 1 and Form 2 crystals, Form 1, Form 2 and Form 4 crystals, or Form 2 and Form crystals. 4. Mixtures of Form 1 and Form 2 AD crystals can be present in pharmaceutical formulations or be manufactured, and typically those mixtures comprise at least about 70% of Form 1, usually at least about 90%, but in some cases up to about 70% of that mixture may comprise Form 2 and / or AD. amorphous.

Crystal Forms of AD The AD prepared and recovered as described (Starrett et al., J. Me d. Ch em. (1994) _1_9: 1857 - 1864) and how it is recovered from a column of silica gel in a methanol solution (approximately 4) and methylene chloride (about 96%) by rotary evaporation under reduced pressure at about 35 ° C, is precipitated as a non-crystalline or amorphous solid. It has now been discovered that AD can be prepared in a crystalline form. In the present, several crystalline forms of AD have been identified. They have been characterized through several methods, usually by XRD and CBD thermogram. Researchers commonly use XRD to characterize or identify crystalline compositions (see, for example, US Pharmacopoeia, volume 23, 1995, method 941, pages 1843-1845, USP Pharmacopeia Convention, Inc., Rockville, MD; Stout et al. , X-Ray Structure Determination, A Practical Guide, MacMillan Co., New York, NY 1968). The diffraction pattern obtained from a crystalline compound is often a diagnostic for a given crystalline form, although weak or very weak diffraction peaks may not always appear in the replication diffraction patterns obtained from successive batches of crystals . This is particularly the case if other crystalline forms are present in the sample, in appreciable amounts, for example, where the crystals of Form 1 have been partially hydrated to form Form 2 crystals. The intensities of relative bands, particularly the values of Low-angle X-ray incidence (2? low), may vary due to the preferred orientation effects arising from differences, for example, in the dominant crystalline form, particle size and other conditions of the measurement. Thus, the relative intensities of the diffraction peaks are not conclusively diagnostic of the shape of the crystal in question. On the other hand, the relative position of the peaks, rather than their amplitude, should be observed to determine whether a crystal of AD is one having the forms described herein. The individual DRX peaks, in different samples, are generally located within approximately 0.3-1 degrees 2? for broad peaks. Broad DRX peaks may consist of two or more individual peaks located fairly close. For acute isolated peaks, the peak is usually within approximately 0.1 degrees 2? in successive analyzes of DRX. Assuming that the same instrument is used to measure the XRD spectrum of a compound in successive XRD analyzes, the differences in the locations of the XRD peaks are mainly due to differences in the sample preparation or the purity of the sample. shows same. When an isolated, acute DRX peak is identified at a certain position located, for example, at approximately 6.9, this means that the peak is at 6-9 ± 0.1. When a broad DRX peak is identified at a particular location, located approximately at a value of 2? determined, does this mean that the peak is at that value 2? ± 0.3. Note that this should not necessarily happen in all bands that are observed in the reference samples of highly purified AD, hereof; even a single band can be diagnostic of a certain crystalline form of AD, for example, 6.9 for Form 1. The identification should focus on the position of the band and on the general pattern, particularly on the selection of the single bands for the bands. different crystalline forms. Additional diagnostic techniques that may be optionally used to identify crystalline AD include differential scanning calorimetry (CBD), melting point measurements, and infrared absorption spectroscopy (IR). CBD measures the thermal transition temperatures at which a crystal absorbs or releases heat when its crystalline structure changes or melts. Thermal transition temperatures and melting points are typically found within approximately 2 ° C in successive analyzes, usually within about 1 degree. When it is mentioned that a compound has a peak of CBD or a melting point at a given value, this means that the type of CBD or a melting point is within ± 2 ° C. CBD provides an alternative means to distinguish between different crystalline forms of AD. Different crystal shapes can be identified, at least in part, based on their different transition temperature profiles. IR measures the absorption of infrared light, caused by the presence of particular chemical bonds associated with groups in a molecule that vibrates in response to light. The CBD and / or IR can thus provide physicochemical information that can be used to describe AD crystals.

Form 1 Single-crystal X-ray crystallography was used to characterize the AD of Form 1. Cell constants and orientation matrix obtained from a least-squares refining using the measured positions of 3242 reflections with I > lOs in the interval 3.00 < 2? < 45.00 ° corresponded to a monoclinic cell centered at C specified as follows: a = 12.85 Á, b = 24.50Á, c - 8.28 A, ß = 100.2 °, Z = 4, spatial group Cc. The DRX pattern of Form 1 usually shows a peak (s) at about 6.9, typically at about 6.9 and about 20.7, or, more typically, at about 6.9, about 15.7 and about 20.7 and ordinarily at least about 6.9, about 11.8, about 15.7 and about 20.7. Typically the DRX peak at approximately 6.9, or usually, either (1) this peak plus one or two additional peaks or (2), the peak at approximately 6.9 plus one or two different peaks coupled with differential scanning calorimetry data or melting point data is sufficient to distinguish Form 1 crystals from other forms, or to identify Form 1 itself. The spectrum of Form 1 commonly has peaks at about 6.9, about 11.8, about 12.7, about 15.7, about 17.2, about 20.7, about 21.5, about 22.5, and about 23.3. The DRX pattern of Form 1 usually shows a peak (s) in either (or a combination) of approximately 6.9 and / or 11.8 and / or 15.7 and / or 17.2 and / or 20.7 and / or 23.3. Figure 1 shows a typical X-ray crystal diffraction pattern of Form 1. However, it should be understood that Figures 1-26 are only exemplary and that diagnostic representations of other crystalline AD preparations can depart from these representations. Form 1 AD is anhydrous, contains little water, or can not be detected. In general, the Form 1 crystals will ordinarily contain less than about 1%, typically less than about 0.5%, and usually less than about 0.2% water. In addition, the Form 1 crystals will ordinarily contain less than about 20%, typically they will contain less than about 10%, often less than about 1%, and usually less than about 0.1% non-crystalline AD. Often, Form 1 crystals will not contain noncrystalline AD that can be detected by CBD, DRX or by microscopy with polarized light at 100X magnification. The AD of Form 1 is, typically, substantially free of crystallization solvent, ie, typically less than about 1%, usually less than about 0.6%, if it is adequately recovered from the crystallization bath, and does not contain solvent molecules trapped in the network. The crystals of Form 1 generally have a mean light scattering size of about 25-150 μm, usually about 30-80 μm. The individual preparations of Form 1 usually contain crystals having a length range of about 1-200 μm and have a typical maximum dimension for individual crystals, in a preparation, of about 60-200 μm. In some Form 1 preparations, approximately 1 to 10% of the crystals in a preparation will have a maximum dimension greater than 250 μm. The crystals of Form 1 shown in Figures 4-10 typically have dominant forms of tablet, plate, needle and / or irregular. Aggregates of Form 1 crystals are also presented with a typical range of diameters of about 25-150 μm. The crystals of Form 1 exhibit an endothermic transmission by CBD at approximately 102 ° C (see Figure 2) and an IR spectrum essentially as that shown in Figure 3. Different preparations of crystals of Form 1 have a bulk density of about 0.15-0.60 g / mL, usually about 0.25-0.50 g / mL, with a surface area of about 0.10-2.20 m2 / g, usually about 0.20-0.60 m2 / g. The AD of Form 1 is thus characterized by a peak spectrum of DRX, using Cu-Ka radiation, expressed in degrees 2? in some (or combination) of approximately 6.9 and / or 11.8 and / or 15.7 and / or 20.7 and an endothermic transition, as measured by differential scanning calorimetry, at approximately 102 °. The AD of Form 1 is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? at 6.9J0.1, 11.8 ± 0.1, 15.7J0.1, 17.2J0.1, 20.7 ± 0.1 and an endothermic transition peak, measured by differential scanning calorimetry at 102.0 + 2 ° and / or an endothermic initiation at 99.8+ 2 .

Form 2 The XRD pattern of Form 2, an example of which is depicted in Figure 11, usually shows a peak (s) approximately at 22.0, typically at about 18.3 and about 22.0, or, more typically at about 9.6, approximately 18.3 and approximately 22.0 and ordinarily to at least approximately 9.6, approximately 18.3, approximately 22.0 and approximately 32.8. Typically, three or four of these characteristic XRD peaks, or usually, either (1) four peaks or (2) two or three of these peaks coupled with differential scanning calorimetry data or melting point data, is sufficient to distinguish Form 2 crystals from other forms, or to identify Form 2 itself. The XRD pattern of Form 2 usually shows a peak (s) in some (or a combination) of about 8.7-8.9, about 9.6, about 16.3, about 18.3, about 18.9, about 19.7, about 21.0- 21.3, approximately 21.4, approximately 22.0, approximately 24.3, approximately 27.9, approximately 30.8 and approximately 32.8. Form 2 crystals are AD dihydrate, and usually contain crystallization solvent that is essentially undetectable, different from water. Shape 2 crystals will ordinarily contain less than about 30%, typically less than about 10%, often less than about 1%, usually less than about 0.1% non-crystalline AD. Generally, the crystals will not contain non-crystalline AD that can be detected by CBD, DRX or microscopy with polarized light with a magnification of 100X. The Form 2 crystals typically have an average size of about 15-85 μm by light scattering, ordinarily about 25-80 μm. The individual preparations of Form 2 usually contain crystals having a length range of about 1-300 μm. The crystals of Form 2 have an endothermic transition of CBD at about 73 ° C (see Figure 12) and an IR spectrum substantially as shown in Figure 13. The AD of Form 2 is thus characterized by a peak of XRD spectrum, using Cu-Ka radiation, expressed in degrees 2? to any (or in a combination) of about 9.6 and / or about 18.3 and / or about 22.0 and / or about 32.8 and an endothermic transition, as measured by differential scanning calorimetry, at about 73 °. The Form 2 AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 9.6 + 0.1, 18.3 ± 0.1, 22.0 + 0.1, 24.3 + 0.1 and 32.8 ± 0.1 and an endothermic transition peak, as measured by differential scanning calorimetry at 72.70 + 2 ° and / or an endothermic initiation at 69.5 + 2 °.

Form 3 The XRD pattern of Form 3, such as that shown in Figure 14, usually shows a peak (s) at about 8.1, typically at about 8.1 and about 25.4, or more typically at about , 8.1, approximately 19.4 and approximately 25.4. Typically any one or two of these three characteristic XRD peaks, or usually, either (1) three or four of these peaks or (2) two or three of these peaks coupled with differential scanning calorimetry data or melting point data , it is sufficient to distinguish Form 3 crystals from other forms, or to identify Form 3 itself. The Form 3 AD has an endothermic transition at approximately 85 °, as measured by differential scanning calorimetry (Figure 15). The spectrum of Form 3 commonly has peaks in either (or a combination) of about 8.1, about 8.7, about 14.1, about 16.5, about 17.0, about 19.4, about 21.1, about 22.6, about 23.4, about 24.2, about 25.4, and about 30.9. Unlike forms 1 and 2, the crystals of Form 3 contain approximately one equivalent of methanol in the crystal lattice. Methanol is typically donated by the crystallization solvent. However, Form 3 contains essentially no other detectable solvent or water. Shape 3 crystals will ordinarily contain less than about 20%, typically less than about 10, often less than about 1%, usually less than about 0.1% non-crystalline AD. The crystals will not contain non-crystalline AD that can be detected by CBD, DRX or microscopy with polarized light at a magnification of 100X. The crystals of Form 3 typically have an average size of about 20-150 μm by light scattering, ordinarily about 30-120 μm. The individual preparations of Form 3 usually contain crystals having a length range of about 1-300 μm.

Form 4 A DRX pattern of Form 4, such as that shown in Figure 16, usually shows a peak (s) at about 26.3, typically at about 26.3 and about 31.7, or typically at about 26.3, about 31.7. and about 15.2, or usually at about 26.3, about 31.7, about 15.2 and about 21.0. Typically these four characteristic XRD peaks, or usually any of (1) three of these peaks or (2) two or three of these peaks coupled with differential scanning calorimetry data or melting point data, is sufficient to distinguish the crystals of Form 4 in other ways, or to identify Form 4 itself. The Form 4 AD has endothermic transitions at approximately 121 ° C, and approximately 148 ° C, as measured by differential scanning calorimetry (Figure 17). The spectrum of Form 4 commonly has peaks in either (or in a combination) of about 9.8, about 15.2, about 15.7, about 18.1, about 18.3, about 21.0, about 26.3, and about 31.7. The Form 4 AD is thus characterized by a peak of the XRD spectrum, using Cu-Ka radiation, expressed in degrees 2? in either (or in a combination) of about 15.2 and / or about 21.0 and / or about 26.3 and / or about 31.7 and an endothermic transition, as measured by differential scanning calorimetry, at about 121.3 ° and about 148.4 °. The Form 4 AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 9.8 ± 0.1, 18.1 ± 0.1, 21.0 + 0.1, 26.3 + 0.1 and 31.7 + 0.1 and an endothermic transition peak, as measured by differential scanning calorimetry at 121.3 + 2 ° and 148.4 + 2 °.

Crystal Salts of Organic and Inorganic Acids s Figures 18-26 show the XRD spectra obtained from crystalline salts, or alternatively, complexes of AD and organic and inorganic acids. These salts are a salt or hemisulfate complex (Figure 18), a salt or hydrobromide complex (Figure 19), a salt or nitrate complex (Figure 20), a salt or mesylate complex (CH3S03H) (Figure 21), a salt or complex of ethyl sulfonate (C2H5SO3H) (Figure 22), a salt or complex of β-naphthyl sulfonic acid (Figure 23), a salt or complex of α-naphthalic acid (Figure 24), a salt or complex of the (S) -fonophonic acid (Figure 25) and a salt or complex of succinic acid (Figure 26). These XRD spectra show a number of peaks that characterize the compounds and allow each compound to be identified from other crystal forms.

Figure 18 shows that the salt or hemisulfate complex has distinctive DRX peaks, in degrees 2 ?, in any (or combination) of about 8.0, about 9.5, about 12.0, about 14.6, about 16.4, about 17.0, about 17.5-17.7 , approximately 18.3, approximately 19.0, approximately 20.2, approximately 22.7, approximately 24.1 and approximately 28.2. The salt or complex has a melting point of about 131-134 ° C. It is thus characterized by having four of these distinctive DRX peaks at about 12.0, about 14.6, about 16.4 and about 17.5-17.7. The compound can be further characterized by having three or four of these DRX peaks and by having a melting point of about 131-134 ° C. The hemisulfate of AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? at 8.0 + 0.1, 12.0 + 0.1, 14.6 + 0.1, 16.4 + 0.1 and 17.5-17.7 + 0.3 and a melting point of 131-134 ± 2 ° C.

Figure 19 shows that the hydrobromide salt or complex has distinctive DRX peaks, in degrees 2 ?, in any (or combination) of about 13.2, about 14.3, about 15.9, about 17.8, approximately 20.7, approximately 21.8, approximately 27.2 and approximately 28.1. The salt or complex is decomposed with heating at about 196-199 ° C. In this way it is characterized by having four distinctive DRX peaks at about 13.2, about 14.3, about 17.8 and about 28.1. The compound can be further characterized by having three or four of these DRX peaks and by decomposing with heating at about 196-199 ° C. AD hydrobromide is alternatively characterized by a type of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 13.2 + 0.1, 1 4. 3 J 0. 1, 17.8 + 0.1, 20.7 + 0.1 and 27.2 + 0.1 and a decomposition point of 196- 199 ± 2.0 °. Figure 20 shows that the nitrate salt or complex has distinctive DRX peaks, in degrees 2 ?, in any (or combination) of about 8.0, about 9.7, about 14.1, about 15.2, about 16.7, about 17.1 approximately, about 18.3 , approximately 18.9, approximately 19.4, approximately 20.0, approximately 21.2, approximately 22.3, approximately 23.2, approximately 24.9, approximately 27.6, approximately 28.2, approximately 29.4 and aapprrooxxiimmaaddaammeennttee 3322..66 .. The salt or complex decomposes with heating to approximately 135- 136 ° C. In this way it is characterized by having four distinctive DRX peaks at about 14.1, about 23.2, about 29.4 and about 32.6. The compound can be further characterized by having three or four of these DRX peaks and by having a melting point of about 131-134 ° C. The nitrate of AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 8.0 + 0.1, 14.1 + 0.1, 23.2 ± 0.1, 29.4 + 0.1, and 32.6 + 0.1 and a decomposition point of 135-136 ± 2 °. Figure 21 shows that the salt or mesylate complex has distinctive DRX peaks in grades 2? in any (or combination) of about 4.8, about 15.5, about 16.2, about 17.5, about 18.5, about 20.2, about 24.8, about 25.4 and about 29.5. The salt or complex has a melting point of about 138-139 ° C. In this way it is characterized by having four distinctive DRX peaks at about 4.8, about 15.5, about 20.2, about 24.8. The compound can be further characterized by having three or four of these DRX peaks and having a melting point of about 138-139 ° C. The AD mesylate is alternatively characterized by a peak of the obvious XRD spectrum using Cu-Ka radiation, expressed in degrees 2? at 4.8 + 0.1, 15.5 + 0.1, 16.2 + 0.1, and 24.8 + 0.1 and a melting point of 138-139 + 2 °. Figure 22 shows that the ethyl sulfonate salt or complex has distinctive DRX peaks, in degrees 2?, In any (or combination) of about 4.4, about 8.8, about 18.8, about 23.0-23.3 and about 27.3. The salt or complex has a melting point of about 132-133 ° C. In this way it is characterized by having four distinctive DRX peaks at about 4.4, about 8.8, about 18.8 and about 27.3. The compound can be further characterized by having three or four of these DRX peaks and by having a melting point of about 132-133 ° C. The ethyl sulfonate of AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 4.4 + 0.1, 8.8 + 0.1, 18.8 + 0.1, 23.0-23.3 + 0.3 and 27.3 + 0.1 and a melting point of 132-133 + 2 °. Figure 23 shows that the salt or complex of β-naphthyl sulfuric acid has distinctive DRX peaks, in degrees 2 ?, in any (or combination) of about 9.8, about 13.1, about 16.3, about 17.4, approximately 19.6, approximately 21.6-22.3, approximately 23.4, approximately 24.1-24.5 and approximately 26.6. The salt or complex has a melting point of about 156-157 ° C. In this way it is characterized by having four distinctive DRX peaks at about 13.1, about 17.4, about 23.4 and about 26.2. The compound can be further characterized by having three or four of these DRX peaks and by having a melting point of about 156-157 ° C. The β-naphthylene sulfonate of the AD is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation, expressed in degrees 2? to 9.8 + 0.1, 13.1 ± 0.1, 17.4 + 0.1, 23.4 + 0.1 and 26.2 + 0.1 and a melting point of 156-157 + 2 °. FIG. 24 shows that the salt or complex of the acidic amino acid has distinctive DRX peaks, in degrees 2?, In any (or combination) of about 8.3, about 9.8, about 11.5, about 15.6, about 16.3, approximately 16.7-17.4, approximately 19.6, approximately 21.0, approximately 22.9, approximately 23.7, approximately 25.0 and approximately 26.1. The salt or complex has a melting point of about 122-128 ° C. In this way it is characterized by having four distinct DRX peaks at about 9.8, about 15.6, about 19.6 and about 26.1. The compound can be further characterized by having three or four of these DRX peaks and by having a melting point of about 122-128 ° C. The α-naphthylene sulfonate of AD, is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation expressed in degrees 2? to 9.8 + 0.1, 15.6 + 0.1, 19.6 + 0.1, 21.0 + 0.1 and 26.1 + 0.1 and a melting point of 122-128 + 2 °. Figure 25 shows that the salt or complex of the (S) -can for phonic acid has distinctive DRX peaks, in degrees 2 ?, in any (or combination) of about 5.4, about 6.5, about 13.7, about 15.5, about 16.8 -17.2, approximately 19.6, approximately 20.4-20.7, approximately 23.1, approximately 26.1, approximately 27.5, approximately 28.4, approximately 31.3 and approximately 32.2. The salt or complex has a melting point of about 160-161 ° C. In this way it is characterized by having four distinctive DRX peaks at about 5.4, about 6.5, about 13.7 and about 16.8-17.2. The compound can be characterized further by having three or four of these DRX peaks and by having a melting point of about 160-161 ° C. The (S) -canforsul fonate of AD, is alternatively characterized by a peak of the obvious DRX spectrum, using Cu-Ka radiation expressed in degrees 2? to 5.4 + 0.1, 6.5 + 0.1, 13.7 + 0.1, 16.8-17.2 + 0.3 and 19.6 + 0.1 and a melting point of 160-161 + 2 °. Figure 26 shows that the salt or complex of succinic acid has distinctive DRX peaks, in degrees 2?, In any (or combination) of about 4.7, approximately 9.5, about 10.6, about 14.9, about 16.3, about 17.4, about 17.9, approximately 19.9, approximately 20.8, approximately 22.1, approximately 23.9-24.2, approximately 26.5, approximately 27.6 and approximately 28.2. The salt or complex has a melting point of about 122-124 ° C. In this way it is characterized by having four distinctive DRX peaks at about 4.7, about 9.5, about 14.9 and about 17.4. The compound can further be characterized by having three or four of these DRX peaks and by having a melting point of about 122-124 ° C. AD succinate is alternatively characterized by a peak of the obvious XRD spectrum, using Cu-Ka radiation expressed in degrees 2? to 9.5 + 0.1, 14.9 + 0.1, 16.3 + 0.1, 17.4 + 0.1 and 23.9-24.2 + 0.3 and a melting point of 122-124 + 2 °. The embodiments of the invention include compositions comprising a crystalline salt, for example, a salt as described above, of adefovir dipivoxil and a pharmaceutically acceptable excipient (s). Other embodiments include a process for preparing a pharmaceutically acceptable composition by contacting an alkaline salt, for example a salt as described above, of adefovir dipivoxil, and a pharmaceutically acceptable excipient (s). Other embodiments include the product produced by the process of contacting a crystalline salt, for example, a salt as described above, of the adefovir dipivoxil and a pharmaceutically acceptable ex-cyclis (s).

Methods for AD Synthesis Diagram A below shows a representative process flow diagram for producing AD and AD crystals from Form 1.

Diagram A (EtO): P (0) H step 1 1. (CH? O) n / Et3N I Ip-TsCl -O 1 you can increase or decrease the scale of the process steps shown in Diagram A and described later, if desired.

Methods for the synthesis of p-t or luensu 1 fon i lox ime t i 1 fo s Diethyl fonate In one embodiment, the synthesis of p-toluensul foni loximet i 1 diethyl phosphonate, shown in Diagram A, step 1, is described as follows. In a reactor having an inert atmosphere, for example, nitrogen, a mixture of diethyl phosphite (0.8 kg), para-formaldehyde (0.22 kg), and triethylamine (0.06 kg) in toluene (2.69 kg) is heated to 87 ° C (from 84 to 110 ° C) for two hours, with stirring, then heated to reflux and maintained at reflux for one hour, until the end of the reaction. The completion of the reaction is inspected by Thin Layer Chromatography (TLC) (no traces of diethyl phosphite can be detected) and confirmed by 1 H NMR it is shown that there is no more than 1% of the phosphite peak of diethyl ad 8.4-8.6 ppm. The solution is cooled to approximately 1 ° C (from -2 to 4 ° C) and p-toluensul fonyl chloride (1.0 kg) is added and then triethylamine (0.82 kg) is added slowly to no more than 10 ° C (approximately 3 to 6 hours in an exothermic reaction). The resulting mixture is heated to 22 ° C (19-25 ° C) and stirred for at least 5 hours (typically about 16-24 hours), until the reaction is complete. The completion of the reaction is inspected by TLC (until no traces or any chloride of oluensul f oni 1 o chloride can be detected) and confirmed by XH NMR (the doublet of p-to luensul chloride is no longer detected. fond 1 oad 7.9 ppm). The solids are removed by filtration and rinsed with toluene (0.34 kg). The combined washings and the filtrate are washed, each twice with water (1.15 kg each time), or optionally with a water sequence (1.15 kg), 5% aqueous sodium carbonate solution (3.38 kg), and two times with water (1.15 kg each time). In the case that emulsion is present, brine may be added to the first organic / water mixture. The organic phase, which is no more than 50 ° C, is distilled in va cuo (up to LOD not greater than 10% and a water content, by titration KF (Karl Fischer), no greater than 0.5%), producing the title compound as an oil of approximately 85-95% purity, exclu of toluene. The oil can become viscous when cooled.

Methods for the Synthesis of 9- (2-hydroxyethyl) adenine In one embodiment, the synthesis of 9- (2-Hydroxiet i 1) adenine, shown in diagram A, step 2, is described as follows. In a reactor having an inert atmosphere, for example, nitrogen, sodium hydroxide (6 g) is added to a liquid paste of adenine (1.0 kg) and molten ethyl carbonate (0.72 kg, m.p. 37-39 ° C), in DMF (2.5 kg) and the mixture is heated to 125 ° C (from 95 ° C under reflux) with stirring until the reaction is complete (approximately 3 to 9 hours if the temperature of the mixture is at 110 ° C to reflux temperature, or approximately 15 to 48 hours if it is 95 to 110 ° C). The completion of the reaction is inspected by HPLC (not exceeding 0.5 % adenine). The mixture is cooled to below 50 ° C and diluted with toluene (3.2 kg). The resulting slurry is cooled to 3 ° C (0-6 ° C) and stirred for at least 2 hours.

The liquid paste is filtered and the filter cake is washed twice with cold toluene (0 to 5 ° C) (0.6 kg each time). The filter cake is dried in a temperature of 35 to 70 ° C (not more than 2% toluene, by XH NMR or LOD) and optionally triturated, yielding the title compound as a white powdery solid. whitish Methods for the Synthesis of 9- [2- (Diethylphosphonomethoxy) ethyl] adenine This compound is prepared using a composition comprising sodium alkoxide (alkyl of 1 to 6 carbon atoms) and 9- (2-hydroxyethyl i) adenine. The sodium alkoxide, typically sodium t-butoxide or sodium i-propoxide, is contacted with 9- (2-hydroxy-1-yl) adenine in a solvent such as DMF, at a temperature of about 20 to 30 ° C. for approximately 1-4 hours. The synthesis typically provides good results with a molar equivalent of 9- (2-hydroxy-1-yl) adenine and about 1.2-2.2 molar equivalents of sodium alkoxide. In one embodiment, the synthesis of 9- [2- (Diethylphosphonomethoxy) ethyl] adenine, shown in Diagram A, step 3, is described as follows. In a reactor having an inert atmosphere, for example, nitrogen, a liquid paste of 9- (2-hi rox ieti 1) adenine (1.0 kg) and DMF (4.79 kg) is heated to about 130 ° (125-135 °). ) for a time of 30 to 60 minutes. The contents of the reactor are cooled rapidly with vigorous stirring to about 25 ° (20-30 °) and tert-butoxide (0.939 kg) is added in portions for a time of about 1-3 hours while maintaining vigorous stirring and the temperature of the contents is maintained at approximately 25 ° (20-30 °). The stirring and the temperature are maintained for a time of approximately 15-45 minutes after all the sodium t-butoxide has been added. Then the reactor contents are cooled to approximately -10 ° (-13 to 0 °), and a solution of p-toluensul foni 1-oxymethi-1-diethyl fonate (2.25 kg in a pure base) in DMF is added ( 1.22 kg) for a time of approximately 5-10 hours. The mixture is maintained at about -5 ° (-10 to 0 °), which is typically about 0.5 to 2 hours after the final portion of p-toluensul foni loxime ti 1-diethyl phosphonate has been added. The completion of the reaction is inspected by HPLC (no more than 3% of 9- (2-hydroxy et i1) adenine remaining). Glacial acetic acid (0.67 kg) is added and the temperature of the container is controlled so that it does not exceed more than 20 °. The mixture which is at about 22 ° (15-25 °) is stirred for a time of about 15 to 45 minutes. The quenched mixture is immediately concentrated until the distillation is stopped and the contents are then cooled to below 40 °. Dichloromethane (16.0 kg) is added and the content at 20 ° (15-25 °) is stirred for at least 1 hour. If the DMF content against total solids (NaOTs (sodium tosylate), NaOAC, Et2PMEA) is greater than 20% (by XH NMR) the mixture is concentrated in va cuo until the distillation is stopped, the content is cooled to below 40 ° C, dichloromethane (16 kg) is added and the reactor content at about 20 ° (15-25 °) is stirred for at least 1 hour. Diatomaceous earth (0.5 kg) is added and the content, which is approximately 20 ° (15-25 °), is stirred for at least 1 hour. The solids are removed by filtration and rinsed three times with CH2C1 (approximately 1 kg each time). The filtrate and the rinses, at no more than 80 °, are concentrated in vat until the distillation is stopped, the content of the reactor is cooled to below 40 °, dichloromethane (5.0 kg) is added to the residue and the content at approximately 25 ° (20-40 °) it is stirred to dissolve the solids. The resulting solution, at no more than 80 °, is concentrated until the distillation is stopped. Dichloromethane (7.0 kg) is added and the content at about 25 ° (20-40 °) is stirred to dissolve the solids. If the content of DMF, compared to the PMEA of diethyl is greater than 12%, the mixture to not more than 80 ° is concentrated in va cuo, the content is cooled to below 40 °, dichloromethane (7.0 kg) is added and the content at about 25 ° (20-40 °) is stirred to dissolve the solids. The mixture is washed with water (0.8 kg) at about 25 ° (22-30 °) by stirring for a time of about 15-45 minutes. The phases are allowed to separate for 4 hours and then they are separated. The aqueous phase is re-extracted twice with dichloromethane (1.5 kg per wash) by stirring for a time of about 15-45 minutes and the solution is maintained at about 25 ° (22-30 °)., followed by allowing the phases to separate for at least 2 hours. The combined organic compounds, at no more than 80 °, are then concentrated in vacuo until the distillation is stopped. Toluene (3.0 kg) is added, stirred at about 25 ° (22-30 °) for a time of about 15-45 minutes and the resulting mixture, not more than 80 °, subjected to azeotropic distillation in a vacuum. Toluene (3.0 kg) is added and the mixture is heated to about 80 ° (75-85 °), stirred for a time of about 15-45 minutes, cooled to below 30 ° for a time of about 60- 90 minutes and then cooled to approximately 0 ° (from -3 to 6 °). After at least 12 hours at about 0 ° with slow stirring, the resulting liquid paste is filtered and the filter cake is rinsed three times with cold toluene (approximately 0 to 6 °) (approximately 0.2 kg per rinsing). The wet cake is dried at about 50 ° (35 to 65 °) and the dried product is ground. The drying of the product is inspected for the removal of water (no more than 0.3% of water is detected by KF titration). The inert atmosphere is maintained through step 3.

Method for the PMEA Synthesis In one embodiment, the PMEA synthesis, shown in Diagram A, step 4, is described as follows. A reactor having an inert atmosphere, for example, nitrogen, a mixture of PMEA of diethyl (1.00 kg), acetonitrile (2.00 kg), and bromine trimet i 1 if 1 year (1.63 kg) is heated and maintained at the temperature reflux for a time of about 1-3 hours with stirring, until the reaction ends.

The completion of the reaction is inspected by 31P NMR or HPLC (diethyl PMEA is not detected and no more than 2% monoethylen PMEA is detected). The solution at a temperature less than or equal to 80 ° C is distilled in vacuo to a semi-solid which is collected in water (2.00 kg) and heated to approximately 55 ° C (52-58 ° C) for a time of approximately 30-60 minutes with stirring to dissolve all solids. The resulting mixture is cooled to approximately 22 ° C (19-25 ° C) is adjusted to pH 3.2 with aqueous sodium hydroxide solution, the contents are heated to approximately 75 ° C (72-78 ° C) until the consistency Arrange (approximately 15-120 minutes), cool to approximately 3 ° C (0-6 ° C) and stirred for at least 3 hours (3-6 hours). The liquid paste is filtered and the filter cake is rinsed with water (1.00 kg). The wet cake is suspended in water (3.75 kg) and the suspension is heated to about 75 ° C (72-78 ° C) with vigorous stirring. After stirring for about 2 hours, the liquid paste is cooled to about 3 ° C (0-6 ° C) and stirred for at least another 2 hours. The liquid paste is filtered and the filter cake is sequentially rinsed with two portions of water (0.50 kg per rinse) and two portions of acetone (1.00 kg per rinse). The isolated solid is dried at no more than about 90 ° C to a low water content (no more than 0.5% water detected by KF titration), to provide PMEA as white crystals. The product is crushed to a fine particle size.

Methods for AD Synthesis An exemplary method for preparing AD comprises suspending 1 mole equivalent of PMEA in a volume of about 5.68-56.8 equivalents of NMP / equi-span PMEA, and then suspending PMEA, adding about 2-5 molar equivalents, often about 2.5-3.5, usually about 3 molar equivalents, of triethylamine ("TEA") to the solution, using gentle to moderate agitation. Then about 3-6 molar equivalents are added, often about 4.5-5.5 molar equivalents, usually about 5 equivalents, of chloromethyl pivalate, to obtain a reaction mixture. Usually the reaction mixture is prepared at room temperature. The reaction mixture is heated to maintain a temperature of less than 66 °, typically about 28-65 °, usually between about 55-65 ° for a time of about 2-4 hours to carry out the reaction. The time necessary to heat the reaction mixture to about 28-65 ° is not critical and may vary depending on the volume of the reaction mixture and the ability of the apparatus used to heat the mixture. Gentle or moderate agitation keeps the solids in suspension during the reaction and this minimizes extensive spattering of reagents in the reaction vessel. This method results in a product comprising AD produced by the process of reacting the listed reagents, typically under the given conditions. In one embodiment, the conversion of PMEA to AD, shown in Diagram A, step 5, is described as follows. In a reactor having an inert atmosphere, for example nitrogen, a mixture of 1-methyl-1-dihydro-1,3-diol (3.15 kg), PMEA (1.00 kg), triethylamine (1.11 kg), and chloromethyl pivalate (2.76). kg) is heated to approximately 60 + 3 ° C (not more than 66 ° C) and stirred using moderate agitation for a time less than or equal to 4 hours (1-4 hours) until the end of the reaction, as indicated by 31P NMR or HPLC (no more than 15% mono (POM) PMEA). The mixture is diluted with isopropyl acetate (12.00 kg), cooled to 25 + 3 ° C, and stirred for about 30 minutes. The solids are removed by filtration and washed with isopropyl acetate (5.0 kg). The combined organic components are washed twice with water (3.70 kg per wash) by means of moderate agitation of the mixture at a mixing temperature of 25 + 3 ° C for a time of about 15-45 minutes. The combined aqueous washings are re-extracted twice with isopropyl acetate (4.00 kg per extraction) at a temperature of the mixture of 25 + 3 ° C by stirring for 15-45 minutes. The organic components combined at 25 + 3 ° C are washed with water (1.80 kg) by stirring for 15-45 minutes and then the organic components at a temperature of about 35 ± 5 ° C (not more than 40 ° C) are They concentrate approximately 40% of the original volume. After a filtration with clarification (1 μm filter) and a subsequent rinse with 1.5 kg of isopropyl acetate, the concentration of the organics in va cuo is concluded until in the organic compounds there is a pale oil at about 35+ 5 ° C (not more than 50 ° C). The oil typically comprises about 6-45% AD, usually about 30-42%.

Methods for AD Crystallization The crystallization of AD from organic oil is usually achieved by (1) the use of a relatively low volume of NMP in the synthesis reaction of the AD as compared to the amount of PMEA present as reagent, ie, less than about 10 L of NMP per gram of PMEA, and / or (2) by minimizing the amount of acetate of isopropyl which is entrained in the organic oil after vacuum distillation by allowing sufficient time for vacuum distillation, i.e., usually at least about 4-6 hours. The aggregate of the initial reaction materials, e.g., NMP or PMEA, in the oil, may represent approximately 2-20% of the crystallization solution, but is generally less than about 1-2%. When the crystals are prepared from an organic oil, about 20-45%, often about 30-42%, and usually about 35-42% of AD is present in the oil before adding the solvents for crystallization. The AD optionally crystallizes from a solution on s aurated. Nucleation occurs in these overstressed solutions, and easily leads to crystal formation. Nucleation rates typically increase when the degree of supersaturation and temperature increase. Overstressed solutions are typically prepared by changing the temperature (usually by decreasing it), by evaporating the solvent or by altering the solvent composition, for example, by adding a miscible solvent or a poor solvent. Combinations of these methods also generate solutions of AD s tured, for example, using evaporation under reduced pressure both to cool the solution and to increase the concentration of the solute. The crystalline AD is prepared by allowing the formation of crystals in an AD composition, usually from a solution of AD in a crystallization mixture containing at least about 6%, typically at least about 30%, usually at least about 35% , from AD. The crystallizations would ordinarily be carried out by preparing a solution of AD comprising about 6-45% of AD and about 55-94% of the crystallization solvent. The upper limit of solubility of the AD is about 10-41% for most of the crystallization solvents at room temperature. The AD is not freely soluble in some crystallization solvents, for example, the solubility of AD in di-n-butyl ether is less than about 0.3 mg / mL, and adding these solvents to a solution of AD increases the degree of saturation or supersaturation of the solution. Usually, organic solutions containing an amount of AD that is close to the upper solubility limit in the crystallization solvent (s) are used. The lower amount, approximately 6%, is the minimum amount of AD needed in a solution to produce crystals consistently. Certain solvents, for example, methanol or CH2C1, may contain more than about 50% AD. The temperature at which the crystallization is carried out is not critical and may vary, as the crystallization process usually takes place spontaneously in a temperature range. Crystallization at temperatures above about 35 °, especially at 45-50 ° can result in reduced yield and / or an increase in impurities associated with the crystals. The crystallizations are generally carried out at temperature ranges from about -5 ° to about 50 °, often at about 0-35 °, usually about 4-23 °. Optionally, crystallization temperatures below about -5 ° can be used to increase the crystal yield or to increase the speed of crystal formation., but a low temperature process can result in increased byproducts. In this way, it is generally more convenient and economical to use solvents, either at approximately ambient temperatures (approximately 15-23 °) or at typical cooling temperatures that can easily be reached by most cooling devices or methods (approximately 0- 4) . When a solution contains relatively low AD concentrations, ie, of about 10-20%, crystallization at a relatively low temperature, i.e., about 0-15 ° will often increase the crystal yields.

Heating the solution containing AD and the crystallization solvent (s) to a point above room temperature, preferably up to about 35 °, appears to facilitate crystallization, presumably increasing the nucleation rate. The time to heat the crystallization mixture to about 35 ° is not critical and may vary according to the capacity of the apparatus used, generally for a period of about 20-45 minutes. The heating is then discontinued and the temperature reduced by cooling or allowing the temperature to fall for a time of about 10-120 minutes. During this time crystals are formed and continue to form for a period of at least about 4-36 hours. Crystallization usually starts immediately or slightly after the crystallization mixture has reached 35 °. Usually the crystallizations are carried out allowing the temperature to drop to approximately 0-23 ° C after the solution reaches 35 °. Crystallizations performed with or without mild to moderate agitation, typically with gentle agitation, routinely provide good results. The appreciable crystallization usually occurs in a period from about 5 minutes to about 72 hours and about 10-16 hours routinely provide good results regardless of the solvents used. The crystallization time is not critical and may vary, although very short crystallization times (approximately 30-90 minutes) may result in a recovery of reduced AD. When crystallization solvents are added to the reaction mixtures, which contain other organic solvents, for example NMP, crystallization usually starts immediately once the temperature has reached about 35 ° or less and the solution has become cloudy. The crystallizations are carried out in a common apparatus of a laboratory or a production plant, for example, in round bottom flasks, in Erlenmeyer flasks, in stainless steel reactors or in glass-lined reactors. Usually the crystallizations will be carried out using a standard laboratory scale apparatus or a commercial scale manufacturing apparatus, for mechanical agitation and temperature control. When crystallization systems containing two different solvents are used, the most polar solvent is usually first added to the AD, followed by the addition of the less polar solvent. Optionally, the undissolved components, if any, of the solution are removed, after the first crystallization solvent has been added, for example, by filtration or centrifugation. For example, when acetone and di-n-butyl ether are used to prepare the Form 1 crystals from an organic solution containing AD and the components of the AD synthesis reaction, usually acetone is usually added first. Similarly, n-butanol could be added before adding di-n-butyl ether or ethyl acetate could be added before the di-n-propyl ether. A solution containing the first polar solvent can become cloudy because the precipitation of mono (POM) PMEA may be present. The mono (POM) PMEA can be removed after the solution by standard physical methods, for example, filtration, or centrifugation, followed by the addition of the second solvent, for example, di-n-butyl ether. The crystallization solvents that are used herein to prepare the Form 1 crystals, generally contain less than about 0.2% water. When a significant amount of water is present in the crystallization solvent, that is, approximately 1-2%, the crystallization process produces variable amounts of Form 2 crystals, which are also recovered together with the Form 1 crystals. amount of water that is present in a crystallization reaction is optionally reduced through conventional means, which include the use of anhydrous reagents or by drying solvents, using molecular sieves or other known drying agents. Optionally, the amount of water that could be present in organic solutions containing AD, for example, of AD synthesis reactions containing by-products and solvents such as the organic oil described above, is reduced by the use of an azeotropic cosolvent such as isopropyl acetate, to reduce the water before adding the crystallization solvents. In one embodiment, the crystallization of the AD of Form 1, shown in Diagram A, step 6, is described as follows. The pale oil containing the AD described above is dissolved in acetone (1.0 kg), heated to + 3 ° C, and diluted with di-n-but-1-yl ether (5.00 kg) in about 4 portions while holding at a temperature of approximately 32-38 ° C and. moderate agitation. The clear solution is cooled to about 25-30 ° C for a time of about 30-60 minutes (no more than 90 minutes), seeded with a small amount of Form 1 AD crystals (approximately 5 g), and the The content is then cooled to 22 + 3 ° C for a time of about 30-60 minutes (no more than 90 minutes) while maintaining moderate agitation. The moderate agitation of the mixture is continued at 22 + 3 ° C for a minimum of about 15 hours. The resulting liquid paste is filtered and the filter cake is washed with a pre-mixed solution of acetone (0.27 kg) in di-n-butyl ether (2.4 kg) (1: 9 v / v). The wet solids are further purified, optionally, by adding pre-mixed acetone (0.57 kg) and di-n-butyl ether (4.92 kg), maintaining the temperature of the contents at 22 ± 3 ° C for a time of approximately 15-24 hours. with agitation. The solids are then filtered, and the filter cake is washed with pre-mixed acetone (0.27 kg) and di-n-butyl ether (2.4 kg). The filter cake is maintained at a temperature less than or equal to 35 ° C (approximately 25-35 ° C) and dried in va cuo for a time of about 1-3 days (LOD not greater than 0.5%), producing AD of Form 1 as a. powdery white to whitish solid. The dried product is crushed. The invention includes methods for preparing Form 2 crystals. Form 2 crystals are conveniently prepared by hydrating the Form 1 crystals, although the hydrate can be obtained by crystallizing the AD from crystallization solvents containing an amount of water that does not interfere with crystallization but provides the necessary hydration water. Water may be present as ice, liquid water or water vapor. Typically it is placed in physical contact with the Form 1 crystals under conditions for the formation of the Form 2 crystals. The Form 1 crystals are optionally contacted with steam in a gas such as air, carbon dioxide or nitrogen, at a relative humidity of at least about 75% to obtain the complete conversion of the crystals from Form 1 to Form 2. The crystals of Form 1 are usually contacted with air at a relative humidity of at least about 75% for a time of about 1-10 days at a temperature of about 18-30 ° or typically at room temperature to obtain complete conversion to Form 2. However, Form 1 crystals are essentially non-hygroscopic at a relative humidity of 54% in air at room temperature, with no increase in water content after 13 days of exposure.

The process of hydrating the crystals from Form a 1 to Form 2 generates compositions comprising a mixture of AD crystals of Form 1 and Form 2 wherein the proportion of Form 1 crystals varies from about 100% to 0%, and the rest of the AD is in Form 2. Thus, the proportion of Form 2 crystals increases from 0% to 100% during the conversion process. These compositions may comprise formulations such as tablets. As mentioned above, the crystals of Form 2 are also prepared by carrying out the crystallization of the AD in the presence of water, for example, wherein approximately 2-5% of the water is present in the solvent (s) of crystallization otherwise used to produce AD of Form 1. Crystallization occurs essentially as described above for Form 1 crystals, for example, for a time of about 4-36 hours at a temperature of about 0-23 °. These preparations may contain some Form 1 crystals, but some of the residual Form 1 crystals are optionally converted to Form 2 crystals by exposure to water vapor as described above., or adding enough additional water to the crystallization solvent. The crystals of Form 3 are usually prepared by allowing the crystals to grow in a solution of AD in anhydrous methanol. The AD is obtained in methanol, by mixing sufficient non-crystalline or crystalline AD in methanol, for a time of about 10-15 minutes at room temperature or as necessary to dissolve the solid AD and obtain a solution having at least about 100-150. mg of AD / mL of methanol. The solubility of AD in methanol, at room temperature, is greater than 600 mg / mL. The crystallization then proceeds for about 4 hours to about 48 hours at a temperature of about -5 ° to about 25 °, usually at about 0-23 °. The crystals obtained using isopropyl acetate as the only crystallization solvent are mainly rods which can be relatively long, that is, they measure up to approximately 500 μm in length, a few needles being also present. Figure 8 shows rod Shaped crystals of approximately 20-500 μm in length obtained by crystallization from isopropyl acetate at temperatures above about 15 °. Crystallization from AD solutions and from saturated or somewhat unsaturated AD solutions is optionally facilitated or enhanced by adding seed crystals of AD to the solution, but seed crystals are not required. For example, the AD of Form 1 is obtained by adding a small amount of crystalline AD of Form 1 to an organic solution as described above, for example, organic oil to which crystallization solvent has been added, but without heating to 35 °. Seed crystals facilitate the formation of Form 1 crystals. Form 2 and Form 3 crystals can be obtained similarly by seeding suitable solutions with the respective crystal form, for example, an organic solution containing ethyl acetate and about 2% of water for Form 2 crystals or a saturated solution of AD in anhydrous methanol for Form 3 crystals. The amount of crystals used for seeding is optionally varied to obtain optimum results. Generally, approximately 0.1-01.0 g of crystals per liter of the solution for the reaction of the AD is sufficient. Optionally crystalline AD can be recrystallized as desired, for example, to increase the purity of the crystals. For example, Form 1 AD is essentially recrystallized by the same methods used to prepare the Form 1 crystals described above. For example, recrystallization using acetone and di-n-butyl ether is achieved by dissolving crystalline AD in acetone, about 0.2-0.4 g / mL at about 20-35 °, followed by optionally removing undissolved components, for example, filtering or centrifuging the solution, which is usually cloudy. An undissolved component is typically the mono (POM) PMEA. The solution is then heated to a temperature of about 35-40 ° and about 5.2-6.2 mL (usually about 5.7 mL) of hot di-n-butyl ether (about 35-40 °) is added per 0.2-0.4 g of crystals. that have been used initially in recrystallization. The recrystallization mixture is then allowed to cool to room temperature for a time of about 4-4.5 hours. The recrystallization mixture will be cooled to room temperature if relatively small volumes are used, e.g., about 1-3 liters. The time to cool the mixture is not critical and may vary. The recrystallization generally starts a little after the addition is complete and mixing the di-n-butyl ether and then the recrystallization is allowed to proceed for a time of about 4-36 hours, usually about 6-24 hours. . Usually an additional production of crystals is obtained from recrystallization at room temperature for a time of about 4-36 hours, cooling the recrystallization mixture to about 4-10 ° and allowing the mixture to stand for a time of about 1-6 hours at the reduced temperature. Usually the amount of AD that is used in a recrystallization will be sufficient to form a saturated or closely saturated solution, ie, approximately 0.4 g / mL using acetone. The dissolution of the AD in acetone ends approximately in a time of 2-8 minutes using moderate agitation. The remaining, undissolved material, after this initial mixing period, is eliminated and discarded, followed by the addition of a second, less polar solvent, of the pair of solvents, to the mixture containing the first crystallization solvent. Optionally -crystals of Form 1 are recrystallized using a single solvent such as acetone. In this embodiment, sufficient crystals in the solvent are dissolved at room temperature to produce a saturated or closely saturated solution, followed by removal of the undissolved components. The mixture is heated to 35 ° and allowed to cool as described for recrystallization, using the solvent pair of acetone and di-n-butyl ether.

Recrystallization of the Form 2 crystals will proceed as described for recrystallization of the Form 1 crystals but will use Form 2 crystals dissolved in the recrystallization solvents. The Form 1 crystals which are obtained from the recrystallization are optionally converted to Form 2 crystals as described herein for the conversion of the crystals from Form 1 to Form 2. The recrystallization of the crystals of Form 2 to the Form 1 can also be achieved. In this case, molecular sieves or other solvent drying means can optionally be used to limit the amount of water that is present after the Form 2 crystals are dissolved in the first solvent and during the recrystallization process. The crystals of Form 2 can also be recrystallized using solvents containing approximately 1 to 2% water to directly obtain Form 2 crystals. A recrystallization of Form 3 is carried out in methanol, in the same manner described herein for the preparation of Form 3 crystals. A methanol solution, saturated or nearly saturated, is used to prepare the crystals, ie, at least about 0.6 g / mL of AD. Optionally, salts are prepared from the addition of acid of certain organic and inorganic acids with the basic center in the AD adenosine. Generally, acid salts are prepared by standard methods, including the dissolution of the free base of AD in an aqueous, aqueous and alcoholic or aqueous and organic solution, containing the selected acid or counterion of the acid, optionally allowing crystallization and optionally accompanied by evaporation, agitation or cooling of the solution. The free base is usually reacted in an organic solution containing the acid or counterion, in which case the salt is usually directly separated or the solution can be seeded with crystals or the solution can be concentrated to facilitate the precipitation of the solution. Salt. Modes include solutions comprising AD, a solvent, usually a crystallization solvent, and a sulfonic acid such as arylsulfonic acid of 6 to 16 carbon atoms, an ether sulfonic acid of 4 to 16 carbon atoms or an acid to which 1 phoni co of 1 to 16 carbon atoms. The embodiments also include solutions comprising the AD, a solvent, usually a crystallization solvent, and a carboxylic acid, such as tricarboxylic acid, a dicarboxylic acid or a monocarboxylic acid, and any of those carboxylic acids comprise about from 1 to 12 carbon atoms.

Pharmaceutical Formulations and Administration Routes The compositions of the invention comprising crystalline AD, typically of Form 1, (hereinafter referred to as the active ingredients), are administered through any appropriate route according to the condition to be treated, the Suitable routes include oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (which includes subcutaneous, intramuscular, intravenous, int, intrathecal, intrathecal and epidural.) Generally, compositions of the invention they are administered orally, but compositions containing crystalline AD can be administered through any of the other routes mentioned above.While it is possible for AD to be administered as a pure compound, it is preferable to present it as a pharmaceutical formulation. The present invention comprises AD, together with one or more pharmaceutically acceptable excipients or carriers ("excipient"). s acceptable ") and optionally other therapeutic ingredients. The excipient (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be harmful to the patient. The formulations include those suitable for topical or systemic administration, which include oral, rectal, nasal, buccal, sublingual, vaginal or parenteral administration (which includes subcutaneous, intramuscular, intravenous, int radiomic, intrathecal and epidural). The formulations are in a unit dosage form and are prepared by any of the methods well known in the pharmacy art. These methods include the step of bringing the active ingredient into association with the excipient carrier which constitutes one or more of the auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with any of the carriers either liquid or finely divided solid carriers, or both, and then, if necessary, drying or shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as sachets, capsules or tablets, each containing a predetermined amount of the active ingredient.; as a powder or granules; as a solution or a suspension in an aqueous liquid; or in a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste.

Formulations of the invention include compositions comprising AD and an acceptable excipient. These excipients include binders, diluents, disintegrants, preservatives, dispersants, glidants (anti-adherents) and lubricants. These compositions optionally comprise unit dosages including tablets and capsules. Such compositions optionally comprise tablets containing about 5-250 mg of AD, usually about 5-150 mg, including tablets comprising about 60 mg or 120 mg per tablet. Those tablets optionally comprise about 1-10% binder, about 0.5-10% disintegrant, about 50-60% diluent or about 0.25-5% lubricant. These compositions also comprise wet granules containing liquid, for example, water, AD and one or more acceptable excipients selected from the group consisting of binders, diluents, dispersants and disintegrants. A tablet can be manufactured by compression or molding, optionally with one or more auxiliary ingredients or excipients. The tablets will typically comprise about 5-250 mg of crystalline AD per tablet, usually about 30-120 mg and usually predominantly AD of Form 1, eg, about 60 mg per tablet or about 120 mg per AD tablet of Form 1 , wherein only limited amounts, usually less than about 20%, of Form 2 crystals, other types of crystals or non-crystalline AD are present. Compressed tablets can be prepared by compressing with a suitable machine, AD in a free flowing form such as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert diluent, preservative, dispersing or active agent to the surface. The molded tablets can be produced by molding in a suitable machine, a mixture of the powder compound usually moistened with a liquid diluent. The tablets may optionally be coated and printed, scored, or scored, and may be formulated in such a manner as to provide a slow or controlled release of the active ingredient therein. The embodiments include a product manufactured by the process of compressing a mixture containing crystalline AD, typically Form 1 or Form 2, and an acceptable excipient, for example, dry wet granules containing, for example, lactose, pregelatinized starch, croscarmellose sodium , talc and magnesium stearate. Formulations containing crystalline AD and excipient (s) may also contain L-carnitine or L-carnitine salts, for example, L-carnitine L-tartrate (2: 1). The release of pivalic acid from the portion of p i val or loxime ti of AD i n vi seems to decrease the levels of L-carnitine in patients. Tablets containing L-carnitine L-tartrate and AD can decrease the effect of pivalic acid in the reduction of L-carnitine in patients taking AD. The amount of L-carnitine included will be evident to physicians in view of the degree of reduction that occurs in patients. Typical formulation ingredients for tablets or related dosage forms include one or more binders, diluents, disintegrants or lubricants. These excipients increase the stability of the formulation, facilitate the compression of the tablets during manufacture or the disintegration of the formulation after ingestion. Tablets are typically manufactured by wet granulation of one or more excipients with AD in a mixture, followed by wet grinding of the granules and drying to a loss in drying of about 3% or less. A binder such as pregelatinized starch or povidone, which improves processing, is optionally present at a level of about 1-10%. A disintegrant such as microcrystalline cellulose or a cross-linked cellulose such as solid croscarmellose is optionally present at a level of about 0.5-5% to facilitate the dissolution of the tablets. A diluent such as a monosaccharide or disaccharide is optionally present at a level of about 40-60% to mask the physical properties of the AD or to facilitate dissolution of the tablets. A lubricant such as magnesium stearate, such as silicon dioxide is optionally present at a level of about 0.25-10% to facilitate ejection of the tablets during manufacture. the tablets may optionally contain scavengers such as lysine or gelatin, to entrap formaldehyde that can be released during AD storage. The excipients have been described, for example, in the Monograph for "Pregelatinized Starch", Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994, pages: 491-493; Monograph for "Croscarmellose Sodium", Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994, pages: 141-142; Monograph for "Lactose Monohydrate", Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994, pages: 252-261; Monograph for "Talc", Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994, pages: 519-521; Monograph for "Magnesium Stearate", Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994, pages: 280-282. Typical containers for the storage of Form 1 AD formulations will limit the amount of water that is present in the container. Typically the unit formulations or dosages are packaged with a desiccant such as silica gel or activated carbon, or both. The containers are typically sealed by induction. Packaging with silica gel alone is a sufficient desiccant for the storage of tablets containing AD at room temperature. The AD contains two portions of pi valoyloximet i per molecule. Silica gel is thus convenient as an individual desiccant for compounds such as therapeutic agents that contain one or more pi value moieties. The water permeation characteristic of the containers has been described, for example, in vessels-permeation, Chapter, USP 23, United States Phar acopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, page 1787 (1995). For infections of the eyes or other external tissues, for example the mouth and the skin, the formulations are preferably applied as an ointment or topical cream containing the active ingredient (s) in an amount, for example , from 0.01 to 10% w / w (which includes the active ingredient (s) in a range that is between 0.1% and 5% in increments of 0.1% w / w such as 0.6% p / p, 0.7% w / w etc.), preferably from 0.2 to 3% w / w and most preferably from 0.5 to 2% w / w. When formulating an ointment, the active ingredients can be used with either an ointment, paraffinic, or water-miscible base. Alternatively, the active ingredients can 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, ie 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. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such intensi fi ers of dermal penetration include dimethyl sulfoxide and related analogues. The oily phase of the emulsions of this invention can be constituted of known ingredients and in a known manner. Although the phase may only comprise an emulsifier (otherwise known as an emulsifier), it is desirable that it comprises a mixture of at least one emulsifier with a fat or an oil with a fat-oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a tabl i zant e. It is also preferred to include both an oil and a fat. Together, the emulsifying emulsifier (s) with or without the t abi 1 i zant e (s) form the emulsifying wax and the wax along with the oil and grease form the base of the emulsifying ointment that forms the dispersed oily phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for the use of the formulation of the present invention include Tween ™ 60, Span MR to chetoesteroaryl alcohol to 1 benzyl 1 cohort, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate. The choice of oils or greases suitable for the formulation is based on achieving the desired cosmetic properties. In this way, the cream should preferably be a non-greasy product, that does not stain and that can be washed, with a suitable consistency to avoid the leakage of the tubes or other containers. Monobasic or dibasic, straight-chain or branched alkyl esters such as diisocyanate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, stearate butyl, 2-ethylhexyl palmitate or a mixture of branched chain esters, known as Crodamol CAP, the last three esters being preferred. These can be used alone or in combination, depending on the properties required. Alternatively, high-melting liquids such as soft and white paraffin and / or liquid paraffin or other mineral oils may be used. Formulations suitable for topical administration to the eyes also include eye drops wherein the active ingredient is suspended or dissolved in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in these formulations in a concentration of 0.01 to 20%, in some embodiments from 0.1 to 10%, and in others approximately 1.0% w / w. Formulations suitable for topical administration in the mouth include tablets containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pills containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouth washes containing the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base containing for example cocoa butter or a salicylate. Formulations suitable for nasal administration or for administration for inhalation, wherein the carrier is a solid, include a powder having a particle size, for example, which is in the range of 1 to 500 microns (including sizes of particles that are 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, for example, nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration can be prepared according to conventional methods and can be delivered with other therapeutic agents. Inhalation therapy is easily administered by metered dose inhalers. Formulations suitable for vaginal administration may be presented as weighings, buffers, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, carriers such as are known in the art as appropriate. Formulations suitable for parenteral administration are sterile and include aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the patient in question; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be present in unit dose or multiple dose containers, for example sealed ampoules and flasks with elastomeric stoppers, and may be stored in a freeze-dried condition (lyophilized) that only requires the addition of a sterile liquid carrier, for example water for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. Preferred unit dosage formulations are those containing a daily dose or a unit, secondary, daily dose, as described above, or an appropriate fraction thereof, of an active ingredient. In addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art which are related to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The present invention further provides veterinary compositions containing at least one active ingredient as defined above, together with a veterinary carrier for the same. Veterinary carriers and materials useful for the purpose of administering the composition to cats, dogs, horses, rabbits and other animals may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the animal. active ingredient. These veterinary compositions can be administered orally, parenterally or through any other desired route. The compounds of the invention can be used to provide controlled release pharmaceutical formulations containing a matrix or absorbent material and as an active ingredient one or more compounds of the invention, in which the release of the active ingredient can be controlled and regulated to allow a less frequent dosing or to improve the pharmacokinetic or toxicity profile of the compound. Controlled release formulations adapted for oral administration in which discrete units comprise one or more compounds of the invention, can be prepared according to conventional methods. All references used herein are expressly incorporated by reference with specificity.

The following examples exemplify, in addition to not limiting the invention.

Example 1. Preparation of Form 1 crystals.

A PMEA (27.3 g, 100 mmol) is added to a 500 mL single neck round bottom flask equipped with a magnetic stir bar. To this is added, under nitrogen, N-met i lpir rolidinone (109.3 mL) and triethylamine (50.6 g, 69.8 mL, 500 mmol), and the resulting suspension is stirred vigorously. Chloromethyl pivalate (75.2 g, 72.0 mL, 500 mmol) is added and the suspension under stirring is placed at 45 ° C in an oil bath for 18.5 hours. The resulting thick, light yellow slurry is diluted with isopropyl acetate (1.0 L) and stirred for 1 hour. The solid is removed by filtration (in a Kimax glass funnel with a "C" glass frit) and washed with more isopropyl acetate (250 mL). The washing is combined with the filtrate and this organic phase is extracted with water (200 mL x 2). The aqueous extracts are combined and re-extracted with isopropyl acetate (250 mL x 2). All the organic phases are combined and measure 1975 mL. Isopropyl acetate is added to bring the total volume of the organic phase up to 2.0 L. For the purpose of an internal control over this experiment, the organic phase is divided into two equal portions of 1.0 L. A portion is treated using a treatment of wash with brine and sodium sulfate, while the other portion is processed without those steps (see below). The organic phase sample of 1.0 L for this new procedure is directly concentrated to an oil, using a standard rotary evaporator (Büchi), using a bath at a temperature of 45 ° C and a vacuum of 50-70 mm Hg throughout The procedure. The weight of the oil is 32.4 g, and it appears perfectly clear with non-visible salts present. The oil is diluted with acetone (25 mL) and again a perfectly clear solution with precipitated salts present not visible. After allowing to stand at room temperature for approximately 3 hours, the solution remains perfectly clear. This solution is placed in an oil bath set at 45 ° C and di-n-butyl ether (140 mL) is added slowly maintaining the internal temperature close to 40 ° C. The flask is then removed from the oil bath and allowed to cool to room temperature and stirred for approximately 16 hours at room temperature resulting in the precipitation of Form 1 AD. The solid product is collected by filtration (in a Kimax glass funnel with "M" glass frit) • The solid is washed with a solution (v / v) (40 mL) of 10% acetone in 90% di ether. -n-but i i co and dried in a vacuum oven for 12 hours (at room temperature purging with nitrogen 28 inches of vacuum). This produces 12.2 g (48.8% theoretical yield, based on a 50 mmol scale reaction) of a white solid, identified (HPLC) as AD of 99.8% purity against external standard. The remaining 1.0 L organic phase is used as control for the above results and treated as follows. This organic phase is washed with brine (25 mL), dried over sodium sulfate (25 g, 12 hours drying time) and concentrated as described above. This gives 27.4 g of an oil, which is crystallized, as described above, in acetone (25 mL) butyl ether (135 mL). The solid is collected by filtration and dried as described above, yielding 12.3 g (48.9% theoretical yield) of a white solid, identified (HPLC) as AD of 98.7% purity against external standard.

Example 2. Preparation of Form 1 crystals 9.7 kg of NMP are added at room temperature, to 3. kg of PMEA, in a glass-lined steel reactor vessel of 113.55 liters (30 gallons) (Pfaudler, Rochester NY, model No. P20-30-150-115) and the mixture is stirred moderately, after adding NMP. The moderate agitation used is sufficient to keep PMEA in suspension and prevents splashing of the reactor contents on the walls. 5.6 kg of ASD are added immediately, followed by the addition of 8.3 kg of chloromethyl pivalate. An additional 2.7 kg of NMP is added immediately to wash the waste materials from the transfer lines used to feed the reactor. The temperature is adjusted to approximately 48 ° C and maintained between 38-48 ° C for 18 hours with moderate agitation. After the reaction is complete, 48 kg of isopropyl acetate are added to the reactor at room temperature and the resulting mixture, under moderate agitation, is maintained for one hour at 43-48 ° C, before filtration to remove the solids. (TyVek ™ filter, 39.37 cm (15.5 pig) in diameter, Kavon Filter Products, Wall, NJ, model No. 1058-D). The 30-gallon (113.55 liter) container is then washed through the filter with 12 kg of additional isopropyl acetate. The filtrate is transferred to a 50 gallon steel-lined reactor vessel (Pfaudler, model No. P24-50-150-105) while maintaining the temperature at 43-48 ° C. The temperature is allowed to descend to room temperature during the subsequent steps. The mixture is washed immediately with 22 kg of water with vigorous stirring for about 1.5-2 minutes. Stirring is suspended and the phases are allowed to separate completely (approximately 10 minutes). -The lower aqueous phase (approximately 26 L), is transferred to a 30-gallon glass lined steel reactor vessel. Another 22 kg of water is added to the organic phase found in the 189.25-liter (50-gallon) reactor and the phases are shaken vigorously for about 1.5-2 minutes. The agitation is suspended and the phases are allowed to separate completely (approximately 1 hour 40 minutes). The lower aqueous phase is transferred to the steel reactor vessel lined with 30 gallon glass, which now contains both aqueous washes. 24 kg of isopropyl acetate are added to the aqueous washes in the 30 gallon reactor and the phases are vigorously stirred for approximately 1.5-2 minutes, followed by suspending the stirring for sufficient time to obtain the separation of full phases (approximately 10 minutes). The upper organic phase is retained and mixed with the organic phase previously retained in the 189.25 liter (50 gallon) reactor. 24 kg of isopropyl acetate are added to the aqueous washes in the 30 gallon reactor and the phases are shaken vigorously for about 1.5-2 minutes, followed by suspending the stirring for sufficient time to obtain the separation of full phases (approximately 20 minutes). The upper organic phase is retained and mixed with the organic phase previously retained in the 189.25 liter (50 gallon) reactor. The combined organic phases are then washed with a brine solution (7 kg of water, 3.9 kg of NaCl) with vigorous stirring for about 1.5-2 minutes followed by a suspension of the stirring to allow complete separation of the phases (approx. minutes). The brine phase is discarded. 18 kg of sodium sulphate are added to the reactor and the mixture is stirred vigorously for approximately 1.5-2 minutes and then left to stand for 1 hour. The organic phase weighs 98.5 kg at this point.

The contents of the reactor are then gently stirred and filtered through a bag filter (American Felt and Filter Co, model No. RM CS / S 122). The organic solution containing AD is transferred to a clean reactor of 189.25 liters (50 gallons) and the volatile organic compounds are removed with vacuum distillation between 33-41 ° C to a vacuum of 26-30 pigs of mercury until they have collected 50-55 L of condensate. The organic phase is transferred from the 189.25 liter (50 gallon) reactor to a clean 30 gallon reactor via vacuum filtration through a cartridge filter (Memtec America, Corp. Model No. 910044), containing a spun cotton cartridge, rolled up, and subsequently washed with 8.6 kg of isopropyl acetate. The solution is kept at 5 ° C overnight, then it is concentrated under a vacuum at 26-41 ° C for 3 hours to obtain approximately 7-9 L of oil. 5.4 kg of acetone are added to the oil, whereby a clear solution is obtained. The solution is stirred immediately and heated to 43 ° C and 27 kg of di-n-butyl ether is added at room temperature over a period of about 4 minutes, followed by a warm-up to return to the temperature of 43 °. C. An additional 15 kg of di-n-butyl ether is added for about 4 minutes and the temperature is returned to 43-44 ° C at which time the temperature is allowed to fall to 20 ° C for about 7 hours 15 minutes. During this time AD crystals form in the reactor. The crystals are recovered by filtration (Nutche filter) and dried. 2.40 kg of AD are obtained (45.1%).

Example 3. Preparation of crystals of Form 1.

A 12-L, 3-necked round bottom flask is charged with 546.3 g of PMEA (2 moles), followed by 2.18 L of NMP at room temperature. Slow mechanical stirring starts (sufficient to keep the solid PMEA suspended but without splashing the contents of the flask), to suspend the PMEA and then charge to the 1.39 L flask of TEA, followed by the addition of 1.44 L of pi-chloro-loximetyl ion. The flask is then purged with nitrogen and the reaction is heated at 60 ° C for 30-45 minutes. Gentle stirring is maintained for 2-2.5 hours with the reaction at 60 ° C. The termination of the reaction is determined by HPLC. The reaction is terminated by charging the flask with 7.48 L of cold isopropyl acetate (0-3 ° C), when the theoretical yield obtained from AD reaches 65-68% by area of normalization. Stirring is increased to moderate agitation (moderate vortex but not splashing the contents) and the mixture remains at room temperature for 30 minutes under moderate agitation while the solids (eg, TEA * HC1, mono (POM) PMEA) precipitate from 1 to solution . The reaction mixture is then filtered using a sintered glass funnel (40-60 μm) and the filter cake is washed with 2.51 L of isopropyl acetate at room temperature. The filtrate is extracted twice immediately with 2.0 L of potable water at room temperature. The combined aqueous phases are extracted again twice with 2.51 L of isopropyl acetate (room temperature). All the organic phases are combined and extracted with 985 mL of drinking water. The organic phase is isolated and concentrated in vacuo for about 1-2 hours at a temperature of 35-39 ° C, at a vacuum of about 30 mm Hg to obtain 1.24 kg of yellow oil. The oil is transferred to a 12 L, 3-necked flask and cooled to room temperature for approximately 30 minutes. The flask is charged with 628 mL of acetone at room temperature and then with 3.14 L of di-n-butyl ether. Slow stirring is started and the solution is heated - at 35 ° C for about 5-20 minutes. When the temperature reaches 35 ° C, the heating is suspended and no further increase in temperature occurs. The solution is cooled down to 30 ° C (20-29 ° C) for approximately 30 minutes. During the cooling period Form 1 crystals are formed in the crystallization mixture while maintaining slow stirring, followed by continuous slow stirring for 14-20 hours at room temperature. The crystals are filtered immediately (Tyvek ™ filter) and the filter cake is washed with a 2L solution of 10% acetone and 90% di-n-butyl ether (v / v). The cake is dried at room temperature in a drying oven with nitrogen purge until a constant weight is obtained (approximately 2 days). The yield of AD of Form 1 obtained is 50-54% of theoretical yield of PMEA and the purity is of 97-98.5% by HPLC by normalization area.

Example 4. Preparation of crystals of Form 1.

A three-neck, 3-L, round bottom flask is charged with 273.14 g of PMEA (1 mol) folloby 1.09 L of NMP at room temperature. Slow mechanical stirring (sufficient to keep the suspended PMEA solid but without splashing the contents of the flask) is started to suspend the PMEA and the flask is immediately charged with 0.418 L of TEA (3 equivalents), folloby the addition of 0.72 L of Pi chloride loxiime ti 1 or (5 equivalents). The flask is then purged with nitrogen and the reaction is heated at 60 ° C for 30-45 minutes. The gentle agitation is maintained for 2-2.5 hours with the reaction at 60 ° C. The term of the reaction is determined by HPLC. The reaction is terminated by charging the flask with 3.74 L of cold isopropyl acetate (0-3 ° C) when the theoretical yield of AD reaches 68-70% by normalization area. Agitation is increased to moderate agitation (moderate vortex but not splashing the contents) and the mixture is alloto stand at room temperature for 30 minutes with moderate agitation while the solids (eg, TEA »HC1, mono (POM) PMEA) precipitate -from the solution. The reaction mixture is filtered using a sintered glass funnel (40-60μm) and the filter cake is washed with 1.26L of isopropyl acetate (room temperature). The filtrate is extracted immediately with 1.01 L of drinking water at room temperature for each extraction. The combined aqueous phases are extracted again twice with 1.26 L of isopropyl acetate (room temperature). All the organic phases are combined and extracted once with 492 mL of drinking water. The organic phase is isolated and concentrated in vacuo for about 1-2 hours at a temperature of 35-39 ° C under a vacuum of about 30 mm Hg, to obtain 0.6 kg of yellow oil. The oil is transferred to a 3-neck 3-necked flask and cooled to room temperature allowing the temperature to drop for approximately 30 minutes. The flask is charged immediately with 314 mL of acetone (room temperature) and it is charged immediately with 1. 57 L of ether di-n-but i 1 co. Slow stirring is started and the solution is heated to 35 ° C for about 5-20 minutes. When the temperature reaches 35 ° C, the heating is suspended and no further temperature rise occurs. The solution is cooled to below 30 ° C (20-29 ° C) for approximately 30 minutes. During the cooling period, Form 1 crystals form in the crystallization mixture, while slow stirring is maintained. An additional volume of 1.15 L of di-n-butyl ether at room temperature is added to the crystallization mixture. The moderate agitation is continued at room temperature for approximately 16 hours. The crystals are then filtered (Tyvek ™ filter) and the cake is washed with 1 L of 90% solution of di-n-butyl ether and 10% acetone (v / v) and this solution is then removed by filtration. The cake is dried at room temperature in a drying oven with a nitrogen purge, until a constant weight is obtained (approximately 2 days). The yield of AD of the Form 1 obtained is 55-58% of the theoretical yield of PMEA and the purity is 99-100% by HPLC per standardization area.

Example 5. Preparation of AD crystals using isopropyl acetate as a crystallization solvent. 43.7 mL of NMP are added at room temperature to PMEA (10.93 g) in a nitrogen atmosphere in a 3-neck 500-L flask equipped with a stirring apparatus. The mixture is stirred to suspend the PMEA. TEA (27.9 mL) was then added at room temperature folloby the addition of pi-loxi-ethyl ilo chloride (28.9 mL) at room temperature. The temperature is increased to 45 ° C and the suspension is stirred for 12 hours at 45 ° C. The resulting thick slurry, yellow in color, is diluted with isopropyl acetate (150 mL) at room temperature and stirred vigorously for 75 minutes at room temperature. The solids are removed by filtration with a "C" type sintered glass frit and the solids are washed with 50 mL of isopropyl acetate at room temperature. The solids are combined and washed twice with deionized water using 40 mL per wash. The water washes are combined and re-extracted twice with isopropyl acetate 40 mL per extraction. All the organic phases are combined, they are washed once with 20 mL of deionized water and the aqueous and organic phases are allowed to separate and remain in contact for 2 hours at 17 ° C. During that time it is observed that in the aqueous-organic interface long crystals are formed as bars. The crystals are collected by filtration using an "M" sintered glass frit and dried, yielding 512 mg of long crystals in the form of bars.

Example 6. Analysis of AD by HPLC.

The crystalline Form 1 AD is analyzed by HPLC to evaluate purity, isolate or identify by-products and to exemplify the use of by-products as reference standards for AD. The levels of compounds present by the normalization area method are analyzed. The HPLC analyzes are carried out in a time of 12 hours of preparation of standards or samples. A liquid chromatograph equipped with a fixed volume sample injector, with a variable wavelength absorbance detector and an electronic integrator, with a column (Alltech Mixed Anion Exchange ™ Mode C8, 7μm, 100μ Pore Size) is used. 250 mm x 4.6 mm (internal diameter), Alltech, Deerfield, IL) and security column (20 mm x 4.6 mm (internal diameter), packed dry with C8 Pelvic particles, Alltech, Deerfield, IL). Water of chromatographic quality is used. The chemical compounds used are acetonitrile chromatographic grade (Burdick &Jackson, Muskegon, MI), analytical grade anhydrous potassium phosphate anhydrous (KH2PO «j, Mal 1 inckrodt, Paris, KY), anhydrous potassium dibasic phosphate, analytical grade (K2HPO4 , Mallinckrodt, Paris, KY) and reactive grade ACS phosphoric acid Mallinckrodt, Paris, KY). Aqueous potassium phosphate solutions are filtered (Nylon 66, 0.45 μm membrane filter, Rainin, Woburn, MA) and degassed before use. Equivalents to these compounds and components can also be used. Apparatus and / or reagents can also be used to obtain similar results. Mobile phase A, which consists of a buffer solution of potassium phosphate, pH 6.0: acetonitrile 70:30 v / v, is prepared to mix 1400 mL of 200 mM potassium phosphate buffer, pH 6.0, with 600 mL of acetonitrile. Mobile phase B, which consists of a buffer solution of potassium phosphate, PH 6.0: acetoni tr i lo 50:50 v / v, is prepared by mixing 1000 mL of 200 mM of potassium phosphate buffer, PH 6.0, with 1000 mL of acetonitrile. Before analyzing the samples, the HPLC column is equilibrated with the mobile phase A at 1.2 mL per minute for 1 hour at room temperature. A sample of 5μL of AD (approximately 1 mg / mL of solution) containing the by-products, is analyzed in a run of 25 minutes at room temperature and a flow of 1.2 mL per minute, using 100% of mobile phase A for 1 minute , followed by a linear gradient of 19 minutes at 100% of the mobile phase B. The column is maintained immediately at 100% of mobile phase B for 5 minutes. The sample containing AD is prepared by weighing exactly 25 mg of a sample of AD or by preparing and dissolving the AD in a final volume of 25.0 mL of the solvent in the sample. The solvent of the sample is prepared by mixing 200 mL of potassium phosphate buffer (3.40 g of potassium monobasic phosphate per 1 L of water, adjusted to a pH of 3.0 with phosphoric acid), with 800 mL of acetonitrile and equilibrating at room temperature . The compounds are identified based on their elution times and / or their retention times. The AD usually elutes at that gradient at approximately 9.8 minutes, the monkey (POM) PMEA elutes at approximately 6.7 minutes and the PMEA elutes at approximately 3.5 minutes.

Example 7. Physical Characterization of the crystals of Form 1.

The crystals of Form 1 are analyzed by XRD by loading approximately 100-150 mg of crystals into an aluminum container, which is mounted inside a di frac tome tro (GE model XRD-5 automatic with a Nicolet automation package) . The crystals of Form 1 are explored between 4 and 35 ° 2? at a scanning speed of 0.05 ° for 1.5 seconds by exposure to an X-ray generator operated at 40 KV and at -20 mA, using a standard focus copper X-ray tube (Varican CA-8) with a graphite monochromator (ES Industries) and a scintillation detector. The weighted average value of the wavelengths of the X-rays used for the calculations is CuKa 1.541838 A °. AD crystals of Form 1 exhibit characteristic DRX peaks, expressed in degrees 2 ?, in approximately 6.9, 11.8, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3. An exemplary pattern of DRX for Form 1 is shown in Figure 1. The crystals of Form 1 are also analyzed by differential scanning calorimetry and exhibit a thermogram as shown in Figure 2 with a characteristic endothermic transition at approximately 102.0. °, having a start of approximately 99.8 °. The thermogram is obtained using a scanning speed of 10 ° per minute, under a nitrogen atmosphere. The sample is not sealed in a container in the CBD apparatus and instead analyzed at ambient pressure in the CBD apparatus. The calorimetric scan is obtained using a differential scanning calorimeter (TA Instruments, model DSC 2910 with a model 2200 controller). Approximately 5 mg of AD is used to obtain the thermogram. Differential scanning calorimetry has been described (see, for example, North American Pharmacopoeia Vol 23, 1995, Method 891 Pharmacopoeia Convention U.S.P., Inc., Rockville, MD). The melting point of the crystals of Form 1 is determined by conventional melting point analysis. The analysis is carried out using a Mettier central processor model FP 90 equipped with a measuring cell model FP 81, according to the manufacturer's instructions. The sample is equilibrated for 30 seconds at an initial temperature of 63 ° C, followed by a temperature increase of 1.0 ° C / minute. The crystals of Form 1 melt in the range of 99.1 ° C to 100.7 ° C. The infrared absorption spectrum (IR) of the crystals of Form 1 is obtained using a Perkin-Elmer FT-IR spectrophotometer, model 1650 according to the manufacturer's instructions. A translucent pellet containing about 10% by weight (5 mg) of Form 1 crystals and about 90% by weight of dry potassium bromide (50 mg), (60 ° C under vacuum overnight) is prepared, (IR grade, Aldrich), grinding the two powders together to obtain a fine powder. IR spectroscopy has already been described (see for example the North American Pharmacopoeia, Vol 23, 1995, Method 197, Pharmacopoeia Convention U.S.P., Inc., Rockville, MD; Morrison, R.T. et al, Organic Chemistry, 3rd edition, Allyn and Bacon, Inc., Boston, pages 405-412, 1973). The sample chamber of the spectrophotometer is purged for at least 5 minutes with high purity nitrogen gas at approximately 6 p.s.i. to reduce the absorbance interference of carbon dioxide up to < 3% on a background scan before doing the scan with the sample. The crystals of Form 1 exhibit an infrared absorption spectrum in potassium bromide with characteristic bands expressed in reciprocal centimeters at approximately 3325-3275, 3050, 2800-1750, 1700, 1625, 1575-1525, 1200-1150, 1075 and 875. An exemplary infrared absorption spectrum for Form 1 is shown in Figure 3. The crystals of Form 1 usually appear as an off-white or off-white powder when they are dry. The crystals that are obtained in a certain preparation are polystyrene and have a range of crystalline dominant forms that include tablets, needles, plates and aggregates of tablets, needles and plates. The crystals of Form 1 typically have a size ranging from about 1μ to about 300μm in length and are of irregular tablet form with fractured edges or angular edges.The crystals of Form 1 which are obtained at low temperature, usually at a temperature of about 2-4 ° C, the preparations using acetone and di-n-butyl ether as crystallization solvents, are typically aggregates comprising mainly needles and some plates.Figures 4-7 are photographs showing crystals of Form 1 obtained from crystallization in acetone and di-n-butyl ether at temperatures above 15 ° C. These photographs show crystals in the form of tablets or in the form of plates and in the form of needles They have a size ranging from about 10 μm to about 250 μm in length.Figure 9 shows crystals of Form 1 that are obtained from crystallization in acetone and di-n-butyl ether. 1 co at temperatures between about 2-4 ° C. The photograph shows aggregates of crystals in the form of plates and in the form of needles reaching a diameter of about 30 μm to about 120 μm. The individual crystals in the aggregates have angled edges. It is found that the crystals of Form 1 have a water content of less than 1% by Karl Fischer titration. The water content analysis is performed essentially as described (see for example, North American Pharmacopoeia, 1990, pages 1619-1621, North American Pharmacopoeia convention).

Example 8. Preparation of crystals of Form 2.

The crystals of Form 1 are converted to Form 2 dihydrate by incubation in air at 94% relative humidity for 3 days at room temperature. During the conversion of Form 1 to Form 2, a mixture of crystals of Form 1 and Form 2 is obtained, which increases over time from Form 2 not detectable in the preparation of the initial Form 1. At the end of 3 days of incubation the final preparation of Form 2 contains crystals of Form 1 not detectable.

Example 9. Physical characterization of crystals of Form 2.

The crystals of Form 2 are analyzed by XRD, by the same method that is used for Form 1. The crystals of Form 2 of AD have characteristic peaks of XRD, in degrees 2 ?, to approximately 8.7-8.9, 9.6, 16.3, 18.3, 18.9, 19.7, 21.0, 21.4, 22.0, 24.3, 27.9, 30.8, and 32.8. An exemplary pattern of DRX for Form 2 is shown in Figure 11. The crystals of Form 2 were also analyzed by differential scanning calorimetry by the same method used to analyze the crystals of Form 1 and exhibit a thermogram as the one shown in figure 12, with a characteristic endothermic transition of about 72.7 ° C, having a start at about 69.5 ° C. The melting point of the crystals of Form 2 is determined by conventional melting point analysis. The analysis is performed using the same method as described for Form 1. The crystals of Form 2 melt in a range of 70.9 ° C to 71.8 ° C. The IR spectrum of the crystals of Form 2 is obtained using the same method as described for the crystals of Form 1. The IR spectrum is shown in Figure 13 and exhibits the following characteristic absorption bands, expressed in reciprocal centimeters to approximately 3300-3350, 3050, 2800-1750, 1700, 1625, 1575-1525, 1200-1150, 1075 and 875. These bands are similar to those associated with the crystals of Form 1, but Form 2 shows an enlarged band of an additional OH bond that is associated with water at about 3500. It is found that the crystals of Form 2 have a water content of 6.7% by Karl Ficher titration. The analysis of water content is carried out essentially as described (see North American Pharmacopoeia, 1990, pages 1619-1621, United States Pharmacopeia Convention).

Example 10. Preparation of crystals of Form 3.

Sufficient crystals of Form 1 (approximately 250 mg) are dissolved in anhydrous methanol (approximately 2 mL) at room temperature to obtain a solution. The solution is obtained by mixing for about 10-15 minutes until the crystals dissolve. The solution is allowed to stand without mixing for about 10-48 hours and then the crystals of Form 3 are recovered from the solution.

Example 11. Physical characterization of the crystals of Form 3.

The crystals of form 3 are analyzed by XRD with the same method as used for the crystals of Form 1. The crystals AD of crystalline Form 3 are characterized essentially by having peaks of XRD, expressed in degrees 2 ?, in approximately 8.1, 8.7, 14.1, 16.5, 17.0, 19.4, 21.1, 22.6, 23.4, 24.2, 25.4 and 30.9. An exemplary pattern of DRX for Form 3 is shown in Figure 14.

Example 12 Synthesis and purification of PMEA.

PMEA is used during synthesis and AD and is purified by crystallization to increase the yield of the product and its purity. In a 12 L round neck flask, containing 548.8 g of diethyl PMEA, charged with 637.5 mL of acetonitrile at room temperature. The diethyl PMEA is dissolved by moderate agitation (moderate vortex with little or no splashing of the contents of the flask). The bottle is purged with nitrogen and 803.8 g of bromine is added slowly (approximately 2-5 minutes). The contents of the flask are heated to reflux (65 ° C) for 2 hours to obtain <; 1% remaining monoethylen PMEA through the HPLC normalization analysis area. The volatiles are distilled in < 80 ° C and ~ 20 mm Hg. The flask is then charged with 1500 mL of water at room temperature. The pH of the solution in the flask is adjusted immediately to 3.2 with 25% w / v NaOH. The contents of the flask are then heated to 75 ° C for 2 hours and the contents are then cooled to a temperature of 3 to 4 ° C for 15-20 minutes and maintained at a temperature of 3 to 4 ° C for 3-3.5. hours. The contents of the flask are then filtered with a filter with a glass frit and the cake is washed with 150 mL of cold water (3-4 ° C). The cake is washed and transferred to a clean, 3-neck, 12-necked flask. L, and the flask is charged with 2025 mL of water and heated to 75 ° C and maintained at that temperature for 2 hours. The heating is suspended and the flask is cooled and maintained at a temperature of 3 to 4 ° C for 3-3.5 hours. The contents of the flask are then filtered with a filter with a glass frit and the cake is washed with 150 mL of cold water (3-4 ° C) and then washed with 1050 mL of acetone at room temperature. The cake is dried to a constant weight by heating at a temperature of 65 to 70 ° C to ~ 20 mm Hg. The yield of PMEA obtained is 85.4% with 99% purity either with analysis by normalization area or by HPLC analysis with external standard.

Example 13. X-ray crystallography of a single crystal of Form 1.

Approximately 200 mg of the AD drug from Lot No. 840-D-l are dissolved in 200 mg of acetone. The solution is heated to approximately 60 ° C. Di-n-butyl ether is added at room temperature, slowly, to the solution at 60 ° C, until the first trace of precipitate appears. The mixture is then stirred and reheated to about 60 ° C to form a clear and homogeneous solution. The solution is allowed to cool to room temperature overnight and is maintained at room temperature for about 2 days. The resultant crystals are very smooth, and some have longitudinal dimensions up to 1 mm. The supernatant is decanted and the remaining crystals are washed with a total of about 1 mL of di-n-butyl ether for four cycles to remove the residual supernatant. A crystal having approximate dimensions of 150 x 200 x 320 μm is subjected to analysis, using X-ray diffraction for a single crystal. All measurements are made in a SMART di frac dose of Siemens (Siemens Industrial Automation, Inc. Madison, Wl) with monochrome Mo-Ka radiation with graphite (? = 0.71069 Á). The glass is mounted on a fiberglass using Paratone NMR hydrocarbon oil. The data is obtained at -135 ± 1 ° C. The frames for an arbitrary hemisphere of reciprocal space were collected using scans w of 0.3 ° per frame, counted for 10 seconds per frame. The 5967 integrated reflections, measured at a 2? maximum of 51.6 °, averaged to produce 3205 unique Friedel reflections. (Rint = 0.044). The structure is solved with atoms that are not hydrogen refined tropically. The hydrogen atoms are introduced in ideal position. The final cycle of the least squares refinement of the complete matrix, based on 2438 observed reflections that have I > 3s and 306 variable parameters converge at R = 0.048 (R "= 0.054). The cell constants and a matrix orientation obtained from the least squares refining using the measured positions of 3242 reflections with I > lOs and in the interval of 3.00 < 2? < 45.00 ° correspond to monocyclic cells centered on C, specified as follows: a = 12.85 A, b = 24.50 A, c = 8.28 A, ß 100.2 °, Z = 4, space group Cc. The following tables show data obtained from the study. The AD diagrams are shown in Figures 27 and 28.

Fractional Atomic Coordinates for the AD of Form 1. a The numbers in parentheses denote the standard deviation in the last significant figures Fractional Atomic Coordinates for the AD of Form 1.a (cont.) a Numbers in parentheses denote the standard deviation in the last significant figures Fractional Atomic Coordinates for the AD of Form 1. (cont.) a Numbers in parentheses denote the standard deviation in the last significant figures Fractional Atomic Coordinates for the AD of Form 1.a (cont.) a The numbers in parentheses denote standard deviation in the significant figures.

Figure 29 shows powder X-ray diffraction patterns, for AD of Form 1: (a) Observed and (b) Calculated.

Example 14. Preparation of crystals of the Form.

Dissolve AD of Form 1 (10.05 g) in isopropanol (50 mL) with heating (approximately 35 ° C) and then filter through a glass frit (frit M, ASTM 10-15 μm). The filtrate is added to a solution of stirred isopropanol (49 L) at about 35 ° C containing dissolved fumaric acid (2.33 g) and the mixture is left to passively cool to room temperature. The crystals of Form 4, of AD * fumaric acid (1: 1) are formed spontaneously in the mixture and shortly after the AD solution is added to the isopropanol solution. The crystals are allowed to form for 2 days at room temperature, are recovered by filtration and dried under vacuum under nitrogen atmosphere at room temperature.

Example 15. Preparation of crystals of the Form.

Dissolve AD of Form 1 (1005.1 g) hot (approximately 45 ° C) with isopropanol (3.0 L). The hot AD solution is added for about 20 minutes, with moderate agitation, to a solution of stirred isopropanol (6.0 L) at about 45 ° C, in a 12 L flask, containing dissolved fumaric acid (233.0 g). The temperature of the mixture is maintained between 40 and 45 ° C for 10 minutes and the heating is suspended when a thick precipitate is formed. Several minutes after all the AD solution is added, the mixture becomes cloudy and then, a few minutes later, the precipitate becomes thick, at which time the agitation is suspended (temperature of the mixture of 42 ° C). The precipitate is left to form for 1 hour. Slow stirring is started and continued for about 2 hours, followed by immersion of the 12 L flask in water at room temperature and continued slow stirring overnight to facilitate cooling of the mixture. The precipitate is recovered with a first filtration (TyVek ™ filter) and a second filtration (M glass frit) and dried under vacuum at room temperature in a nitrogen atmosphere.

Example 16. Preparation of crystalline salts of AD from organic and inorganic acids.

AD of Form 1 (500 mg, 1.0 mmol) is dissolved in isopropyl alcohol (5 mL) with heating (< 40 ° C). Acid (1.0 mmol) is dissolved in 2 mL of isopropyl alcohol, or a larger volume is added to the AD solution as needed to dissolve the acid. The solution is stored in a tightly capped scintillation flask at room temperature. In some cases precipitated salts are observed shortly after the solution is capped (approximately 1 minute). For other salts the precipitate begins to form up to several months after the solution is capped. The melting points for all 13 salts are shown below. The XRD data (grades 2?) For nine salts are also shown below. The XRD data show most of the highest intensity peaks for these salts.

Acid melting point spectrum peaks (° C) of DRX hemisulfate 131-134 8.0, 9.5, 12.0, 14.6, 16.4, 17.0, 17.5-17.7 *, 18.3, 19.0, 20.2, 22.7, 24.1, 28.2 HBr 196-199 13.2 , 14.3, 15.9, (with 17.8, 20.7, 21.8, decomposition) 27.2, 28.1 HCl 204-205 ND *** (with decomposition) HN03 135-136 8.0, 9.7, 14.1, (with 15.2, 16.7, 17.1, decomposition) 18.3, 18.9, 19.4, 20.0, 21.2, 22.3, 23.2, 24.9, 27.6, 28.2, 29.4, 32.6 CH3SO3H 138-139 4.8, 15.5, 16.2, 17.5, 18.5, 20.2, 24.8, 25.4, 29.5 C2H5SO3H 132-133 4.4, 8.8, 18.8, 23.0-23.3 *, 27.3 acid 156-157 9.8, 13.1, 16.3, ß "17.4, 19.6, 21.6-naphthylenesulfonic 22.3 *, 23.4, 24.1- 24.5 **, acid 26.6 122-128 8.3, 9.8, 11.5 , a- 15.6, 16.3, 16.7-naphthylenesulfonic 17.4 **, 19.6, 21.0, 22.9, 23.7, 25.0, 26.1 acid 160-161 5.4, 6.5, 13.7, (S) - 15.5, 16.8-17.2 *, camphorsulfonic 19.6, 20.4 -20.7 *, 21.2, 23.1, 26.1, 27.5, 28.4, 31.3, 32.2 fumaric acid 144-145 ND Acid melting point spectrum peaks (° C) of DRX succinic acid 122-124 4.7, 9.5, 10.6, 14.9, 16.3, 17.4, 17.9, 19.9, 20.8, 22.1, 23.9-24.2 *, 26.5, 27.6, 28.2 maleic acid 72-75 ND ascorbic acid 210-212 ND nicotinic acid 192 -193 ND * present as two peaks or as a peak with shoulder ** 3 to 4 peaks are present in a broad peak *** ND = no analysis was performed by XRD Example 17. AD Formulation Form 1 AD is formulated with various excipients in tablets containing 30, 60 or 120 mg per tablet, as follows. mg per 60 mg per 120 mg per I Tableta Tablet Tablet Component%%% P / P mg / tab. P / P mg / tab. P / P mg / tab.

Adefovir dipivoxil 7.5 30.0 15.0 60.0 30.0 120.0 Starch 5.0 20.0 5.0 20.0 5.0 20.0 Pregelatinized, NF Croscarmellose 6.0 24.0 6.0 24.0 6.0 24.0 Sodium, NF1 1 To be incorporated in the dosage form in two portions (intragranular and extragranular) during the manufacturing process. The amount of water added is sufficient to produce adequate wet granulation. Water is removed to a level of no more than 3% loss to drying (LOD).

The tablets containing the AD of Form 1 are made by mixing croscarmellose sodium, pregelatinized starch and lactose monohydrate in a granulator. The water is added and the content is mixed in a granulator until a suitable wet granulation is formed. The wet granulation is milled, dried in a dryer to a moisture content of no more than 3% loss in drying and dried granules are passed through the mill. The milled granules are combined with extragranular excipients, lactose monohydrate, croscarmellose sodium and talc, and mixed in a mixer to obtain a reduced mixture of powder. Magnesium stearate is added, mixed in a mixer and compressed into tablets. The tablets are stored in high density polyethylene or glass bottles with polyester fiber packing material and optionally with a silica gel desiccant.

Example 18. Formulation of AD.

Form 1 AD is formulated with various excipients in tablets weighing 100 mg each and each containing 25 or 50 mg of AD per tablet as follows. The tablets are prepared by wet granulation in a manner similar to that described above.

Content per unit Component% p / p% p / p AD of Form 1 25.0 50.0 Lactose monohydrate, NF 40.5 26.5 Microcrystalline cellulose, NF 31.0 20.0 Croscarmellose Sodium, NF 2.0 2.0 Silicon dioxide, NF 0.5 0.5 Magnesium stearate 1.0 1.0 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (46)

RE IVIND ICATIONS

1. A composition characterized in that it comprises adefovir crystalline dipivoxil.

2. The composition according to claim 1, characterized in that the adefovir crystalline dipivoxil is adefovir-dipivoxil crystalline anhydrous.

3. The composition according to claim 2, characterized in that it comprises a monoclinic cell centered on C, substantially specified as follows: a = 12.85 A, b = 24.50 A, c- = 8.28 A, ß = 100.2 °, Z = 4, group space Cc.

4. The composition according to claim 2, characterized in that it has a peak of the X-ray diffraction spectrum, of the powder, using Cu-Ka radiation, expressed in degrees 2 ?, in approximately 6.9

5. The composition according to claim 4, characterized in that it has an endothermic transition by Differential Scanning Calorimetry (CBD) at approximately 102 ° C.

6. The composition according to claim 1, characterized in that the crystalline adefovir dipivoxil is the hydrated form C2oH32N5? 8P »2H20 of adefovir dipivoxil.

7. The composition according to claim 6 characterized in that it has a peak of the powder X-ray diffraction spectrum, using Cu-Ka radiation, expressed in degrees 2 ?, in approximately 9.6, approximately 18.3, approximately 22.0 and approximately 32.8.

8. The composition according to claim 7, characterized in that it has an endothermic transition by CBD at about 73 ° C.

9. The composition according to claim 1, characterized in that the adefovir dipivoxil crystalline is the solvate form in methanol C2oH32N5? 8P # CH3OH of adefovir dipivoxy lo.

10. The composition according to claim 9, characterized in that it has a peak of the X-ray diffraction spectrum, of the powder, using Cu-Ka radiation, expressed in degrees 2 ?, in approximately 8.1, approximately 19.4, approximately 25.4 and approximately 30.9.

11. The composition according to claim 10, characterized in that it has an endothermic transition by CBD at about 85 ° C.

12. The composition according to claim 1, characterized in that the adefovir crystalline dipivoxil is the salt or complex of fumaric acid C2oH32N508P # C4H404 of adefovir dipivoxil.

13. The composition according to claim 12, characterized in that it has a peak of the X-ray diffraction spectrum, of the powder, using Cu-Ka radiation, expressed in degrees 2 ?, in approximately 9.8, approximately 15.2, approximately 26.3 and approximately 31.7.

14. The composition according to claim 4, characterized in that it has an endothermic transition by CBD at about 148 ° C.

15. The composition according to claim 1, characterized in that it comprises a crystalline salt of adefovir dipivoxil.

16. The crystalline salt according to claim 15, characterized in that the crystalline salt is a salt of an organic acid.

17. The crystalline salt according to claim 15, characterized in that the crystalline salt is a salt of an inorganic acid.

18. The composition according to claim 1, characterized in that the crystalline adefovir dipivoxil is a crystalline salt of adefovir dipivoxil, selected from the group consisting of the hemisulfate, hydrobromide, hydrochloride, nitrate, mesylate, ethane sulfonate, ß-naphthylene sulfonate, sulfonate of a-naphthylene, (S) -canfor sulfonate, succinic acid, maleic acid, ascorbic acid or nicotinic acid.

19. The composition according to the rei indication 1, characterized in that it comprises a pharmaceutically acceptable excipient abl e.

20. A method characterized in that it comprises administering to a subject a highly effective anti-viral amount of the composition according to claim 19.

21. A method characterized in that it comprises contacting a crystallization solvent and adefovir dipivoxil.

22. The method according to claim 21, characterized in that the adefovir dipivoxil is in a solution.

23. The method according to claim 22, characterized in that the crystallization solvent is mixed with the solution to obtain a second solution which is allowed to form crystals.

24. A method characterized in that it comprises the crystallization of adefovir dipivoxil in a solution comprising about 6-45% of adefovir dipivoxil and about 55-94% of a crystallization solvent, wherein the crystallization solvent is selected from the group consisting of (1) ) a mixture of from about 1:10 v / v to about 1: 3 v / v acetone: di-n-butyl ether, (2) a mixture between about 1:10 v / v to about 1: 3 v / v ethyl acetate: di-n-propyl ether, (3) a mixture between about 1:10 v / v to about 10: 1 v / v of tert-butanol: ether di-n-but i 1, (4) a mixture between about 1:10 v / v to about 1: 3 v / v of methylene chloride: ether di-n-but-1, (5) a mixture of about 1:10 v / v to about 10: 1 v / v diethyl ether: di-n-prop i 1 i co ether, (6) a mixture between about 1:10 v / v and about 1: 3 v / v tetrahydr ofurane: ether di-n-but i i co, (7) -a mixture between approximately 1:10 v / v and approximately 1: 3 v / v ethyl acetate: di-n-butyl ether, ( 8) a mixture between about 1:10 v / v and about 1: 3 v / v tetrahydropyran: di-n-butyl ether 1, co (9) a mixture between about 1:10 v / v and about 1: 3 v / v ethyl acetate: diethyl ether, (10) ether t-butyl 1-methyl, (11) diethyl ether, (12) di-n-butyl ether, (13) t- butanol, (14) toluene, (15) isopropyl acetate, (16) ethyl acetate, and (17) a mixture consisting essentially of (A) a first crystallization solvent consisting of a first dialkyl ether of the formula R1 -0-R2 wherein R1 which is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is an alkyl group having 2, 3, 4, 5 or 6 carbon atoms where R1 and R2 which are the same or different, or both R1 and R2 are linked together to form a ring of 5, 6, 7 or 8 member or, as long as the dialkyl ether is not ether methyl-1-yl, and (B) a second crystallization solvent is selected from the group consisting of (a) a second di-alkyl ether of the formula R1-0- R2, wherein the second dialkyl ether is different from the first dialkyl ether, (b) toluene, (c) tetrahydrofuran, (d) t-butanol, (e) ethyl acetate, (f) methylene chloride, (g) acetate of propyl and (h) isopropanol.

25. A method for the preparation of the hydrated form C2oH32N508P * 2 H20 of adefovir dipivoxil, characterized in that it comprises forming adefovir dipivoxil crystals in the presence of water.

26. The method according to claim 25, characterized in that the hydrated form C2oH32N5? 8P »2H2? of adefovir dipivoxil is produced by (1) the hydration of adefovir dipivoxil crystals of the anhydrous crystalline form, and / or (2) the crystallization of adefovir dipivoxil in the presence of water.

27. A method for the preparation of a salt or complex of fumaric acid C2oH32 5? 8P * C4H 0 of adefovir dipivoxil, characterized in that it comprises the formation of crystals comprising adefovir dipivoxil in the presence of fumaric acid.

28. A method for the preparation of adefovir dipivoxil, characterized in that it comprises contacting 9- [2- (fos fonome toxi) et i 1] adenine with chloromethyl pivalate in 1-methyl-1-pyro-1-idinone and trialkylamine and the recovery of adefovir dipivoxil.

29. The method according to claim 28, characterized in that the trialkylamine is triethylamine.

30. The method according to claim 29, characterized in that it comprises contacting 1 molar equivalent of 9- [2 - (fos fonome toxi) eti ljadenine and about 5.6 to 56.8 molar equivalents of 1-methyl-2-piper. 1 idinona.

31. The method according to claim 28, characterized in that it comprises contacting 1 molar equivalent of 9- [2- (phosphomethoxy) e t i l] adenine and about 2 to 5 molar equivalents of triethyl amine.

32. A method characterized in that it comprises contacting 9- [2- (fo s fonome tox i) e t i 1] adenine • containing less than about 2% salt with chloromethyl pivalate.

33. The method according to claim 32, characterized in that the salt is NaBr or KBr.

34. A product characterized in that it is produced by the process of compressing a mixture comprising adefovir dipivoxil of the anhydrous crystalline form a pharmaceutically acceptable excipient.

35. The product according to claim 34, characterized in that the compression results in a tablet.

36. A product of wet granules characterized in that it is produced by the process of preparing wet granules from a mixture comprising a liquid, adefovir dipycodyl of the anhydrous crystalline form and a pharmaceutically acceptable excipient.

37. The product according to claim 36, characterized in that the liquid is water.

38. The product according to claim 36, characterized in that the process further comprises drying the wet granules.

39. A composition characterized in that it comprises a tablet containing adefovir dipivoxil, 20 mg of pregelatinized starch, 24 mg of croscarmellose sodium, lactose monohydrate, 24 mg of talc and 4 mg of magnesium stearate, wherein the adefovir dipivoxil comprises at least about 70 % adefovir dipivoxil of the anhydrous crystalline form.

40. The composition according to claim 39, characterized in that the tablet contains 60 mg of adefovir dipivoxil and 268 mg of lactose monohydrate.

41. The composition according to claim 40, characterized in that the tablet weighs approximately 400 mg.

42. The composition according to claim 40, characterized in that the adefovir dipivoxil comprises at least about 80% adefovir dipivoxil of the anhydrous crystalline form.

43. The composition according to claim 39, characterized in that the tablet contains 120 mg of adefovir dipivoxil and 208 mg of lactose monohydrate.

44. The composition according to claim 43, characterized in that the tablet weighs about 400 mg.

45. The composition according to claim 43, characterized in that the adefovir dipivoxil comprises at least about 80% adefovir dipivoxil of the anhydrous crystalline form.

46. A method for the preparation of 9- [2 - (diethylphosphonomethoxy) ethyljadenine, characterized in that it comprises contacting sodium alkoxide and 9- (2-hydroxyethyl) 1-adenine.