MXPA97005462A - Derived from guan - Google Patents

Abstract

The present invention relates to an anhydrous crystalline form of L-valinate hydrochloride (2- [2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy] and ilo (otherwise known) as valaciclovir hydrochloride) and a procedure for preparing

Description

DERIVED FROM GUANI NA Field of the Invention The present invention relates to a specific crystalline form of the antiviral valacyclovir hydrochloride compound, and to a process for producing the same.

Background of the Invention The compound of 9 - [(2-hydroxyethoxy) methyl] guanine, otherwise known as acyclovir, possesses potent antiviral activity is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses (see, for example, Schaeffer et al, Nature, 272, 583-585 (1978), UK patent No. 1,523,865 and US patent No. 4,199,574). However, acyclovir is poorly absorbed from the gastrointestinal tract during oral administration and this low bioavailability means that it may be necessary to administer multiple large doses, especially Rβ0.025262 for the treatment of less sensitive viruses or infections or to achieve and maintain effective antiviral levels in the plasma. The L-valine ester of acyclovir, especially the L-valinate of (2- [2-amino-1, 6-dihydro-6-oxo-purin-9-yl) methoxyethyl, (otherwise known as valaciclovir) is has shown that it has a much improved bioavailability while retaining the antiviral properties of acyclovir. A preferred form of this compound is its hydrochloride salt which is otherwise known as valaciclovir hydrochloride. The L-valinate ester of acyclovir and its salts including the hydrochloride salt are described in US Patent No. 4,957,924 (see particularly TB Example), European Patent No. 0,308,065 (see particularly example IB and Beauchamp et al. al, Antiviral Chemistry and Chemotherapy, 3 (3), 157-164 (1992) (see particularly page 162, column 1). It has now been found that valaciclovir hydrochloride can exist in various forms, and in addition a form has been discovered. valaciclovir hydrochloride which is anhydrous and crystalline and which surprisingly has particularly good pharmaceutical properties.It is particularly stable and essentially non-hygroscopic.Latches of this crystalline form can be made consistently up to a high purity of the crystalline form, is to say where the proportion of other amorphous and crystalline forms of valaciclovir hydrochloride is limited.In addition, this anhydrous crystalline form has a These storage properties can be easily formulated in pharmaceutical compositions such as tablets and capsules.

Detailed description of the invention According to a first aspect of the invention, valaciclovir hydrochloride is provided in essentially anhydrous crystalline form which substantially includes the following spacing configuration (in Angstroms): . 20 ± 0.08, 8.10 ± 0.06, 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ±, 0.02.

Hereinafter, by "anhydrous crystalline form" according to the invention, is meant a crystalline form having substantially the same diffraction pattern of the X-ray powder as shown in Figures 1 to 3, or having substantially the same configuration of the spacing d as defined above. Any particular crystalline form of a molecule will have its own unique d-space configuration, which can be determined from its powder X-ray diffraction configuration, using the Bragg equation n? = 2 dsen? where: n is the diffraction order (usually 1); ? it is the wavelength of the radiation; d is the spacing d (Angstroms); Y ? is the angle of deflection of the radiation.

It will be appreciated that the measured spacings d may vary slightly depending for example on the degree to which the powder sample is packaged. The invention relates to an anhydrous crystalline form in both the pure form and mixed with other forms of the valaciclovir hydrochloride such as the crystalline hydrated forms. For example, in any batch that contains anhydrous crystalline valaciclovir hydrochloride, there may also be hydrated crystalline forms of the compound. Preferably the purity of the crystal form in any batch of the valacyclovir hydrochloride drug is at least 70% w / w, more preferably at least 80% w / w, still more preferably at least 90% w / w, and still more preferably at least 95% of the anhydrous crystalline valaciclovir clohydrate (as defined above). In an alternative method of determining the purity of the crystalline form, since the anhydrous crystalline form of valaciclovir hydrochloride is essentially free of water of hydration, the proportion of the hydrate forms, of the valacyclovir hydrochloride in any batch of the compound , can be measured by the total content of the hydration water of each batch. Accordingly, in a second aspect of the invention there is provided a valaciclovir hydrochloride having a water content of hydration of not more than 3% by weight (w / w) and which substantially includes the powder diffraction patterns of X-rays. of Figures 1 to 3, or substantially the same configuration of the spacing d shown above.

More preferably, the water content of hydration is not greater than 2% w / w, still more preferably not greater than 1.5% w / w, and still more preferably not greater than 1% w / w, and even more preferably not greater than 0.5% p / p. This water hydration content is measured by the Karl Fischer method which is well known in the art and is described in the U.S. Pharmacopoeia. 1990 on pages 1619-1621, and the European Pharmacopoeia, second edition (1992), part 2, sixteenth issue in v. 3.5.6-1. According to a further aspect, the present invention provides a process for the production of valaciclovir hydrochloride in the anhydrous crystalline form, which comprises treating the valaciclovir hydrochloride with a solubilizing solvent which serves to convert an amount of valaciclovir hydrochloride to the anhydrous crystalline form, having the configuration of the spacing d shown above in the first aspect of the invention; and after that isolate the anhydrous crystalline form. The invention also provides a process for the production of valaciclovir hydrochloride in an anhydrous crystalline form having the spacings d shown above, the process comprising the steps of: a) forming the valaciclovir in solution either in the form of the free base or the salt; b) converting valaciclovir from the free base or a salt thereof (when it is not the hydrochloride salt) to valaciclovir hydrochloride; c) isolate the valaciclovir hydrochloride from the solution and optionally remove the unbound solvent (wet, unsolvated), leaving the valacyclovir hydrochloride = a substantially dry form; d) treating the valacyclovir hydrochloride with a solubilizing solvent which serves to convert an amount of the valaciclovir hydrochloride optionally dried from step c) to the anhydrous crystalline form; Y e) isolate the anhydrous crystalline form.

Valaciclovir can be prepared by any method known in the art, but preferably by the methods described in the references mentioned above (US Patent No. 4, 95, 924, European Patent No. 0,308,065, and Beauchamp et al, Antiviral Chemistry & Chemotherapy 303, 157-164 (1992), the description of US Patent No. 4,957,924 is incorporated herein by reference). Preferably the process starts from the acyclovir whose synthesis is described in Schaeffer et al, Nature, 272, 583-585 (1978), UK patent No. 1,523,865 and US patent No. 4,199,574). Acyclovir is first esterified to its L-valine ester (valaciclovir), using an optionally protected L-valine, for example carbobenzyloxy-L-valine (CBZ-L-valine) in a solvent such as pyridine or DMF in the presence of a binding agent such as N, N '-dicyclohexylcarbodiimide, optionally in the presence of a base such as 4-dimethylaminopyridine as a catalyst. The protecting groups can be removed in a known manner (such as by treatment with formic acid in the presence of 5% palladium on charcoal) following the esterification reaction. The valaciclovir in the form of the free base or of a salt of another acid (for example the formate) can be converted into the hydrochloride salt in the conventional manner, for example by treatment with hydrochloric acid in a solvent. The synthesis of valaciclovir hydrochloride generally leads to the formation of the compound in solution in the reaction mixture from which the ... ism can be separated and purified as a solid product. The valaciclovir hydrochloride can then be dried optionally by conversion into a suspension in acetone and then drying. Several factors influence the crystalline form of the solid product and in accordance with the present invention, the conditions of separation and / or subsequent processing are adjusted to produce valaciclovir hydrochloride as the anhydrous crystalline form. For example, a form of valacyclovir hydrochloride hydrate can be converted to the crystalline form using a suitable solvent under appropriate conditions. Such a suitable solvent which is preferably a water-soluble organic solvent, must be sufficiently solubilizing and must be employed in an amount that allows partial solubilization to effect the conversion and precipitation for example from the hydrated crystalline form to the anhydrous crystalline form of valaciclovir hydrochloride. Advantageously, the solvent is eventually removed by drying under vacuum. Preferably the organic solvent is an alcohol, advantageously a lower alcohol containing 1 to 4 carbon atoms or a lower ketone (containing 3 to 6 carbon atoms). More preferably the lower alcohol is ethanol or a solvent substantially composed of ethanol, for example in the form of denatured alcohol such as SVM or industrial methylated alcoholic beverages. More preferably also, the lower ketone contains water, preferably aqueous acetone such that it has a water content of about 6% to about 12% by weight. Preferably the drug is converted into a suspension in the lower ketone. Initial investigations also suggest that methanol and isopropyl alcohol should also be suitable lower alcohols. According to a particular embodiment of the invention, valaciclovir hydrochloride is formed in solution, for example in ethanol / water, obtained for example by the general method referred to above and valaciclovir hydrochloride is isolated by partial removal of the solvent by distillation followed by precipitation, for example by the addition of acetone. Valaciclovir hydrochloride (such as that isolated after step c above) can be separated at this stage in an unstable solvated form by filtration. This product which is in an undesirable form, can then be dried and processed optionally to the desired anhydrous crystalline form as described below.

The wet valaciclovir hydrochloride obtained from the first isolation (as in step c above) is preferably dried; such as by conversion into a suspension in acetone, then filtering and the wet solid is dried for example in the range of about 30 ° to about 70 ° C to provide the valaciclovir hydrochloride substantially dry. At this time, valaciclovir hydrochloride can contain a high proportion of the dihydrate form which has a theoretical water hydration content of about 9.8%. According to a process for forming the anhydrous valaciclovir hydrochloride, the valaciclovir hydrochloride substantially dry (as obtained above), is mixed with an amount of lower alcohol such as ethanol or denatured alcohol, preferably in an amount of about 15% up to 40% w / w, more preferably in approximate form 17% to 30% w / w. The mixture is then heated for example from about 50 ° C to 70 ° C for several hours. Finally the product is dried under vacuum to remove the residual solvent, for example in the range of about 50 ° C to 70 ° C. The present invention also provides the anhydrous crystalline form of valacyclovir hydrochloride (hereinafter referred to as "the active compound"). ") for use in medical therapy, for example in the treatment of a viral disease in an animal, for example a martiliero such as a human.The compound is especially useful for the treatment of diseases caused by various DNA viruses, such as such as herpes infections, for example, herpes simplex 1 and 2, varicella zoster, cytomegalovirus, Epstein-Barr virus or human herpes virus-6 (VHH-6) as well as diseases caused by hepatitis B. active compound can also be used for the -address of papilloma virus or wart infections and, can be administered additionally in combination with other agents tera agents, for example with zidovudine, to treat retroviral associated infections in particular HIV infections. In addition to its use in human medical therapy, the active compound can be administered to other animals for the treatment of viral diseases, for example to other mammals.The present invention also provides a method for the treatment of a viral infection, particularly a viral herpes disease, in an animal, for example a mammal such as a human, which comprises administering to the animal an effective antiviral amount of the active compound.

The present invention also provides the use of the active compound in the preparation of a medicament for the treatment of a viral infection. The active compound can be administered by any route to be taken for the condition to be treated, but the preferred route of administration is oral. It will be appreciated, however, that the preferred route may vary, for example, with the condition of the patient. For each of the indications and utilities indicated above, the required amounts of the active ingredient (as defined above) will depend on several factors including the severity of the condition to be treated and the characteristics or identity of the patient and by the patient. It will be at the discretion of the doctor or veterinarian to provide the care. However, in general for each of these utilities and indications, a suitable effective dose will be in the range of 1 to 150 mg per kilogram of body weight of the patient per day, preferably in the range of 5 to 120 mg per kilogram of body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to valaciclovir of the free base.) The desired dose is preferably presented as one, two, three or four or more subcoses administered at appropriate intervals throughout the day These sub-doses can be administered in unit dosage forms, for example, containing approximately 50 to 2000 mg, preferably approximately 250, 500, 1000 or 2000 mg of the active ingredient per unit dosage form The following dosing regimens are provided as a guide. treatment of the infection caused by the herpes simplex virus of types 1 and 2: - total daily dose of approximately 1 or 2 g administered in 500 mg twice a day or 1 g twice a day for 5 to 10 days; suppression of infections caused by herpes simplex virus types I and 2: - total daily dose of approximately 250 to 1 g for approximately one to ten years (depending on the patient); treatment of infections caused by the varicella zoster virus (eg herpes or zoster): - total daily dose of approximately 3 g administered in 1 g portions three times a day for seven days; suppression of infections caused by cytomegalovirus: - total daily dose of approximately 8 g administered in 2 g portions 4 times a day; for transplant patients, this daily dose is administered for three to six months during the period of risk; and for HIV positive patients a daily dose is administered as usually indicated to improve the quality of life, for example for two years or more.

The initial results now indicate that valaciclovir can be used in the effective suppression of recurrent genital herpes in a daily dose once a day from about 200 mg to about 1000 mg during an effective treatment period. The most probable daily dosages are 250 mg, 500 mg or 1000 mg. Although it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulation comprises the active ingredient as identified above, together with one or more pharmaceutically acceptable excipients therefor and optionally other therapeutic ingredients. The excipient (s) must be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral administration and can be conveniently presented in a unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier or vehicle which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The formulations of the present invention, suitable for oral administration, can be presented as discrete units such as capsules, granule pouches or tablets (such as an ingestible, dispersible or chewable tablet), 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 a non-aqueous liquid; or as a liquid oil-in-water emulsion or a liquid water-in-oil emulsion. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, dispersing or surface active agent. The molded tablets can be made by molding in a suitable machine the mixture of the pulverized compound moistened with an inert liquid diluent. The tablets may be coated or optionally labeled and may be formulated to provide a slow or controlled release of the active ingredient therein. Preferred unit dosage formulations are those containing a daily dose or a unit daily sub-dose (as described above) or an appropriate fraction thereof., of the active ingredient. It should be understood that in addition to the ingredients mentioned above, the formulations of this invention may include other agents conventional in the art that take into consideration the type of formulation in question, for example those suitable for oral administration may include flavoring agents or agents that mask the taste. The invention is illustrated by the following examples: Example 1 A. 2- [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl-ietoxy] and il-N- [. {Benzoyloxy) carboni 1] -L- val i nato The CBZ-L-valine (170 g) is dissolved in dimethylformamide (DMF) (750 ml) and cooled. A cold solution of N, N-dicyclohexylcarbodiimide (DCC) (156.7 g) in DMF (266 ml) is added and stirred with cooling. Acyclovir (10.1 g) is added in a single portion, and then 4- (dimethylamino) pyridine (9.4 g) is added while cooling is maintained. The mixture is stirred with cooling overnight. A white precipitate of the by-product is then removed by filtration. The filtrate is reduced in its volume by vacuum distillation and the concentrate is treated with water (663 ml) then heated to 70 ° C. The suspension is cooled to 20 ° C, filtered and the solid washed with water. The crude, wet material is then purified by recrystallization from denatured alcohol (1.2 liters) to give the title compound as a wet white crystalline solid (281.5 g).

B. 2 - [(2-amino-l, 6-dihydro-6-oxo-9H-p rin-9-yl) methoxy] ethyl-L-valinate hydrochloride The 2- [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl-N - [(benzyloxy) carbonyl] -L-valinate (175 g) is charged to the aqueous denatured alcohol (335 ml / 795 ml) and heated to reflux. The solution is then cooled to 40 ° C. The suspension is treated with a 5% palladium on charcoal catalyst (35 g wet weight, 50% moisture of water) then formic acid (30.6 ml of 90% w / w) is added for 1 hour. The reaction mixture is stirred for an additional 1 hour, then a second charge of formic acid (19.5 ml) is made and the mixture is filtered to remove the catalyst. The filter cake is washed with denatured alcohol and the combined filtrates are treated with concentrated hydrochloric acid (33.7 ml) and the resulting mixture is concentrated by vacuum distillation. Acetone (1295 ml) is then added over 15 minutes and the suspension is stirred for 1 hour before the product is removed by filtration. The solid is then converted to a suspension with acetone (almost 530 ml), refiltered and dried at 60 ° C in vacuo to give the title compound (1123 g: 81.6%). A sample of 15 g of this material is combined with denatured alcohol (almost 7 ml), until it is moistened and heated with agitation at 60 ° C overnight in a closed container to avoid loss of alcohol and to maintain moisture of the mixture. The mixture is then dried at 60 ° C in vacuo to give the product with the desired morphic form.

Physical data: Karl Fischer value: 0.9% w / w of water.

The diffraction patterns of the X-ray powder of the product of Example IB are shown in Figure 1 of the attached drawings. The d spacings and the additional X-ray diffraction data are shown in Table 1.

Table 1 Peak Angle Peak Configuration Error in I / I? BX No: (degrees) (counts) of the spacing d d (£ A) (%) (A *) 1 3.56 680 24.8 0.5 24 2 8.62 1151 10.25 0.08 39 3 9.42 87 9.38 0.07 3 4 10.86 1438 8.14 0.06 49 12.10 835 7.31 0.06 28 6 13.22 198 6.69 0.05 6 7 14.49 2172 6.11 0.05 75 8 15.12 455 5.85 0.03 15 9 15.90 352 5.57 0.02 12 16.45 1969 5.38 0.02 68 11 16.90 744 5.24 0.02 25 12 17.33 119 5.11 0.02 4 13 18.12 1013 4.89 0.02 35 14 22.71 1429 4.43 0.02 49 20.55 256 4.32 0.02 8 16 21.21 370 4.19 0.02 12 17 21.83 753 4.07 0.02 26 18 22.71 95 3.91 0.02 3 19 23.95 2893 3.71 0.02 100 25.10 171 3.54 0.02 5 21 26.21 1784 3.40 0.02 61 22. 26.89 428 3.31 0.02 14 23 27.08 373 3.29 0.02 12 24 28.02 158 3.18 0.02 5 28.27 161 3.15 0.02 5 26 28.91 391 3.09 0.02 13 27 29.68 191 3.01 0.02 6 28 30.55 502 2.92 0.02 17 29 31.34 110 2.85 0.02 3 31.58 98 2.83 0.02 3 31 32.13 597 2.78 0.02 20 32 32.96 260 2.72 0.02 8 33 33.99 344 2.64 0.02 11 34 34.38 374 2.61 0.02 12 35.12 141 2.55 0.02 4 36 36.78 408 2.44 0.02 14 37 38.71 101 2.32 0.02 3 I / Imax = (peak height / maximum peak height) x 100 The powder sample used to produce the above X-ray diffraction data is prepared by an equivalent method as the powder sample used to produce the X-ray diffraction data of Table 2 (described hereinafter) except that for the above data the following preparation was used to prepare the powder sample. The sample was prepared by grinding 1 g of the sample in a plastic cup using two acrylic beets for 5 minutes with a Chemplex Spectromill equipment. The samples were then again packed against a glass slide to a depth of 2 mm. The X-ray diffraction scan was obtained using a Scintag PADV diffractometer in the gradual scan mode at 0.02 ° per step and a count of 10 seconds per step. The sample holder is centrifuged at 1 revolution per second during the scan. The additional adjustment data is as described below.

X-ray generator: 45 kV, 40 mA Radiation: Copper alpha radiation K Fixed divergent slot: 1 mm Incisive dispersion slot: 2 mm Diffracted dispersion slot: 0.5 mm Reception slot: 0.3 mm Goniometer radius: 235 mm Detector: Twinkling with a monochromator or graphite monochromator.

The peak or maximum intensities are reported as absolute counts of the top of the peak. The intensity units on the X-ray diffraction graph are counts / second. The absolute counts = counts / second x counting time counts / second x 10 seconds. The peak or maximum intensities in the table have been corrected for the contribution of the background and the wavelength of the alpha II X rays of copper K. Light variations are expected in the d spacings based on the specific diffractometer used and the analyst sample preparation technique. A greater variation is expected for peak or maximum intensities, relative. The identification of the exact crystalline form of a drug should be based mainly on the observed d-spacings, giving less importance to the relative peak intensities. To identify the anhydrous crystalline form of valaciclovir hydrochloride, the fifteen most intense diffraction peaks are reasonably characteristic. These peaks are presented at 10.25 ± 0.08, 8.14 ± 0.06, 7.31 ± 0.06, 6.11 ± 0.05, 5.85 ± 0.03, 5.38 ± 0.02, 5.24 ± 0.02, 4.89 ± 0.02, 4.43 ± 0.02, 4.07 ± 0.02, 3.71 ± 0.02, 3.40 ± 0.02, 3.31 ± 0.02, 2.92 ± 0.02, and 2.78 ± 0.02 angstroms. The error in the determination of the d spacings decreases with the increase of the diffraction scan angle or with the reduction of the spacing d. The error of the peak of 10.25 angstrom? it could be approximately ± 0.08 angstroms and the peak error of 2.78 angstroms would be approximately ± 0.01 angstroms for a reasonably aligned diffractometer and for a reasonably prepared sample. The first peak in the line listing at 3.56 degrees is due to the hydrated crystalline phase of valaciclovir hydrochloride and not due to the dehydrated crystalline form. In a further example of the anhydrous crystalline valaciclovir hydrochloride, the following d spacings are obtained: . 20, 8.10, 7.27, 6.68, 6.08, 5.83, 5.56, 5.37, 5.23, 5.10, 4.89, 4.42, 4.31, 4.18, 4.06, 3.91, 3.71, 3.64, 3.54, 3.39, 3.35, 3.32, -3.28, 3.22, 3.18 , 3.14, 3.08, 3.00, 2.97, 2.91, 2.85, 2.77, 2.70, 2.63, 2.60, 2.55, 2.44, 2.42, 2.37, 2.32.

The fifteen most characteristic peaks are 10.20 ± 0.08, 8.10 ± 0.05, 7.27 ± 0.04, 6.08 ± 0.03, 5.83 ± 0. 03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4. 06 ± 0.01, 3.71 ± 0.01, 3.39 ± 0.01, 3.32 ± 0.01, and 2.77 ± 0.01.

Example 2 A. 2 - [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxyethyl-N - [(benzyloxy) carbony1] -L-valinate The CBZ-L-valine (167 g) is dissolved in dimethylformamide (DMF) (750 ml) and cooled. A solution of N, N-dicyclohexylcarbodiimide (DCC) (153.5 g) in DMF (266 ml) is added followed by acyclovir (111.7 g) in a single portion. The 4- (dimethylamino) pyridine (9.4 g) is then added and the mixture is stirred with cooling overnight. A white precipitate of the by-product was then removed by filtration. The filtrate was reduced in volume as above to give the title compound (215.3 g).

B. 2- [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl-L-valinate hydrochloride 2- [(2-amino-1,6-dihydro- 6-Oxo-9H-purin-9-yl) methoxy] ethyl-N - [(benzyloxy) carbonyl-J-valinate (200 g) is charged to the aqueous denatured alcohol (382 ml / 908 ml) and heated to reflux to dissolve the solids. The solution is then cooled to 40 ° C. The suspension is treated with a 50% w / w paste of the 5% palladium on charcoal catalyst and water (40 g) then formic acid (96% w / w: 32.8 ml) is added for 1 hour. The reaction mixture is stirred for an additional 1 hour, then a second charge of formic acid (20.88 ml) is made and the mixture is filtered to remove the catalyst. The filtrate is treated with concentrated hydrochloric acid (38.56 ml) and the resulting mixture is distilled and concentrated under vacuum. Acetone (1480 ml) is then added over 15 minutes and the suspension is stirred for 1 hour before the product is removed by filtration. The solid is then converted to a suspension with acetone (ca. 500 ml), refiltrate and dry at 60 ° C in vacuo to give the title compound (137.75 g: 87.6%). A 10 g sample of this material is combined with denatured alcohol (3.5 ml), heated at 60 ° C for several hours and then the solvent is removed in vacuo to give the product as the desired morphic form.

Result: Valaciclovir hydrochloride in the anhydrous crystalline form was obtained substantially free from other forms of valaciclovir hydrochloride (ie in more than about 90% w / w purity of the anhydrous crystalline form).

Physical data: The diffraction patterns of the X-ray powder of the product of Example IB are shown in Figures 2 and 3 of the accompanying drawings, in which: Figure 2 is an X-ray diffractogram of linear graphical plot; and Figure 3 is an X-ray diffractogram of square root plot. The d spacings and the additional X-ray diffraction data are shown in Table 2.

Table 2 Peak Peak Angle Setting No: (degrees) (counts) of the spacing d I / Imax (%) (A) 1 3.62 2673 2 24.40 7.21 35 119 3 12.26 2 8.64 1910 4 10.22 9.43 25 180 5 9.37 10.86 2 2652 6 8.14 12.12 35 734 7 7.30 13.24 10 615 8 6.68 13.77 8 106 9 6.42 14.50 1 2333 10 6.11 15.14 31 635 11 5.85 15.89 8 511 5.57 12 16.44 7 2652 5.39 13 35 16.90 1267 14 5.24 17.33 17 475 15 5.11 18.13 6 1648 16 4.89 20.05 2172 22 17 4.43 20.56 640 28 18 4.32 21.20 1096 8 19 4.19 21.78 2034 14 4.08 21.90 1384 27 21 4.06 22.66 18 729 22 3.92 23.94 10 7521 23 3.71 24.39 100 1624 24 3.65 25.11 21 967 25 3.54 25.86 13 2460 26 3.44 26.21 32 5127 27 3.40 26.82 67 1892 28 3.32 26.89 25 1927 29 3.31 27.19 25 1429 30 3.28 27.99 19 1156 31 3.18 28.35 15 1076 32 3.15 28.87 14 1722 33 3.09 28.94 23 1529 34 3.08 29.62 20 1274 35 3.01 30.56 17 1673 36 2.92 31.30 22 999 37 2.86 32.25 13 2570 38 2.77 33.04 34 1376 39 2.71 34.00 18 1806 2.63 24 Table 2 - continued 40 34.45 1225 2.60 16 41 35.13 1149 2.55 15 42 36.77 1600 2.44 21 43 38.01 576 2.37 8 44 38.76 729 2.32 10 45 39.52 524 2.28 7 46 40.70 751 2.22 10 47 41.28 870 2.19 11 48 41.88 686 2.16 9 49 42.47 718 2.13 9 50 43.40 548 2.08 7 51 44.53 729 2.03 10 The diffraction paths of the product of Example 2B were run on a Phillips PW1800 Automatic X-ray Powder Diffractometer using a scan or scan from 2 to 45 2? with step or step intervals of 0.02 degrees and an integration time of 4 seconds per step.

Generator settings: 40 KV, 45 mA, 1.2 Cu wavelengths of Cu: 1.54060, 1.54439 A; Step size, sampling time: 0.020 degrees, 4.00 seconds, 0.005 degrees / second; monochromator or monochromator used: yes; divergence slot: automatic (irradiated sample length: 10.0 mm); Maximum angle interval: 2,000 - 45,000 degrees; interval in spacing D: 44.1372 - 2.01289 A; criterion of the position of the peak or maximum value: upper part of the smoothed data; interval of the width of the peak of the crystal: 0.00 - 2.00 degrees; Significance of the minimum peak: 0.75 of maximum intensity: 7621 cts, 1905.3 cps.

The powder sample was prepared as follows: A 1 gram portion of valacíclovir hydrochloride is transferred to a 10 ml polystyrene container Retsch ref 31-762 containing 2 acrylic balls 26-253 and then ground to a very fine powder using a trepan grinding device Retsch MM2 adjusted to 100% power for 5 minutes. The ground powder is charged again in a Philips PW1811 / 10 sample holder which has been placed inverted on a perfectly smooth surface (for example that produced by a glass plate or a highly polished metal sheet). The powder is then packed in the fastener and additional powder is added and packed until the fastener is filled. A bottom plate of the Philips PW 1811 00 apparatus was then fixed or secured in the holder and the complete assembly was then inverted before removing the glass / metal plate in an upward direction to reveal the surface of the smooth sample which was leveled with that of the bra. As illustrated above, the crystalline forms of valaciclovir hydrochloride can be characterized by their X-ray powder diffraction pattern. Figures 1 to 3 show diffractograms of the anhydrous crystalline form of valaciclovir hydrochloride as a linear graph (Figures 1 and 2) and a graph of square root (Figure 3). In each case, the diffractogram shows the counting speed (intensity of the diffracted peak) versus the diffraction angle 2 ?. The linear graph allows a control or facilitated rationing of the maximum intensities while the graph of square root attenuates the peaks, for which it emphasizes the main peaks in the diffraction configuration.

Example 3 Measurements of Hygroscopicity and Stability of Valaciclovir Hydrochloride anhydrous Hygroscopicity: An integrated microbalance system was used to measure water sorption profiles in equilibrium (Model MB300G, VTI Corp.), which weighs approximately 20 mg of valaciclovir hydrochloride, and using the following conditions: Drying parameters: - Temperature: 65 ° C; Heating rate: 1 ° C / minute; equilibrium criterion: 5 μg; sampling interval: 5 minutes Sorption parameters: - Temperature: 25 ° C; equilibrium criterion: 5 μg; Sampling interval: 5 minutes. Data Collection Interval: 2 minutes The sorption / desorption of the water were isotherms noted in Figure 4. The isotherms show that only a small entity of water is absorbed. This absorption is, in effect, exacerbated by the presence of the hydrated crystalline form in the sample, which is consistent with the 0. 9% w / w of water measured by Karl's titration Fischer. The effect of the small amount of this hydrate can be observed more clearly by comparison with the isotherm of Figure 5 which was generated with a crystalline form dehydrated substantially 100%. X-ray powder diffraction: No change between the initial powder configuration and the material configurations stored for 4 weeks at 40 ° C, room temperature / 60% RH (relative humidity), and 40 ° C / 75% of HR. % of water . Initial: 0.9 40 ° C 2 weeks: 0.8 40 ° C 4 weeks: 0.8 T ambient / 60% RH, 2 weeks 1.0 T ambient / 60% RH, 4 weeks 0.9 40 ° C / 75% RH, 2 weeks 1.1 40 ° C / 75% RH, 4 weeks 1.1 Chemical volumetric stability data at four weeks:% w / w on anhydrous basis INITIAL 40 ° C T ambient / 40 ° C / 60% RH 75% RH L-valma: ND (< 0.1%)) ND ND ND 2-Hydroxyethyl valinate hydrochloride: ND (< 0.1%) ND ND: D Acyclovir: 0.9 0.9 0.9 0.9 Guanine: ND (< 0.1%) ND ND ND Isomer D of Valaciclovir: 1.1 1.2 * 1.1 1.2 * HCl Valaciclovir: 97.3 97.8 98.2 97.5 ND = none detected Data rounded to about 1. 1% p / p * There is no significant increase in 2-hydroxyethyl Valinate hydrochloride; the real values between the points of the initial time and of the fourth week are within 0. 03% of each other (which is within the experimental error).

Example 4 Additional studies of hygroscopicity and stability were carried out on a substantially 100% dehydrated crystalline form at 30 ° C / 75% RH (12 months) and 40 ° C / 75% RH (6 months). Samples stored at 30 ° C / 75% RH and at 40 ° C / 75% RH for 12 months and 6 months, respectively, showed no significant change in moisture content (Karl Fischer) or in crystallinity (as measured by X-ray powder diffraction). Using the integrated microbalance system, no more than 0.5% w / w of water is absorbed at 25 ° C at relative humidity of up to 90%. In addition, a separate sample stored for 2.5 months at 25 ° C and 75% RH corroborated the moisture content measured by the integrated microbalance system, ie approximately 0.3% humidity at 75% RH.

The results indicate that the anhydrous crystalline form of valacyclovir hydrochloride is chemically and physically stable. These characteristics give the crystalline anhydrous form good formulation and storage properties, and help to obtain, in a highly reproducible manner, batches of high purity of the crystalline form.

Example 5: Tablet Formulation The following formulations were prepared as follows, using anhydrous crystalline valaciclovir.

* Volumetric density 0.45 g / cc after 50 extractions (crystalline anhydrous form) Example 6: Tablet Formulation The following formulations were prepared as follows using anhydrous crystalline valaciclovir. * volumetric density 0.60 g / cc after 50 extractions (anhydrous crystalline form); Karl Fischer water content = 0.4.

Tablet Preparation for Example 5 Step 1. The following ingredients as shown were sieved with a manual sieve as shown.

Mesh 30 valaciclovir lactose hydrochloride microcrystalline cellulose povidone K30 crospovidone Mesh 60 magnesium stearate colloidal silicon dioxide (CSD) Step 2. The sieved ingredients in the '30 mesh of Step 1 were then combined, excluding povidone, in a V-shaped shell mixer of 0.028 cubic meters (1 cubic foot).

Step 3. 1540 kg of alcohol SD3A (ethanol denatured with 5% methanol) was then mixed with 0.6600 kg of purified water and the povidone, 0.1548 kg, dissolved in 0.6192 kg of the mixed solvents by manual agitation.

Step 4. The mixed powders from Step 2 were then granulated in a Littleford Lodige mixer of 0.028 cubic meters (1 cubic foot) by adding the. povidone dissolved while mixing. 1.315 kg of the most mixed solution are added and the mixture is kneaded for seven minutes in total as shown below.

Suspensions 7 min Shredders 6.5 min Step 5. The granulate from Step 4 is then dried in a Fluid Bed Dryer (Glatt GPCG5) with an inlet air temperature of 50 ° C to an acceptable moisture content of approximately 1.0 to 3.0% L.O.D.

Step 6. The material from Step 5 was then sieved using a Fitz Model M Mill equipped with a 30 mesh screen, with front knives, operating at medium speed.

Step 7. The sifted magnesium stearate from Step 1 is added to the material from Step 6 and combined for 5 minutes using the mixer from Step 2.

Step 8. 2.650 kg of the heavy and sieved lubricated granules (from Step 7) CSD, from Step 1, are then added dispersed by hand and the mixture is combined for 5 minutes in the mixer from Step 2. The mixture is compressed to form tablets in a Manesty Beta press equipped with an oval tool, 19.1 mm x 10.2 mm, at a compression weight of approximately 935.5 mg.

Tablet Preparation for Example 6: Step 1. The core ingredients were sieved with a 20-mesh manual sieve, and then mixed or blended in a V-shaped shell mixer designed appropriately for 10 minutes.

Step 2. The combined or mixed powders from Step 1 were then granulated in a 10-liter high shear mixer (model SP1, 'adding pure water while mixing.Approximately 11-14% water, w / w of the ingredients of the core is then added and the mixture is kneaded for 3 to 4 ^ minutes.

Step 3. The granules of Step 2 are dried in a tray dryer (SP1) (examples 5, 6 and 7) or under vacuum (examples 3 and 4) at a temperature of 50 ° C to an acceptable moisture content. from approximately 1.0 to 2.0% LOD Step 4. The remaining ingredients were sieved through a 20 mesh screen and added to the core ingredients of step 3, and then the mixture was sieved using a computer Cornil Model 197 AS equipped with a 0.1575 cm (0.062") screen.

Step 5. The mixture is then combined in a V-shaped shell mixer designed appropriately for 5 minutes.

Step 6. The mixed granules from Step 5 were compressed on a Manesty Beta Press equipped with a capsule-shaped tool, 18.25 mm x 7.14 mm, at a compression weight of approximately 700 mg and a compression force of approximately 14.5. to the kN.

Step 7. The tablet can then be optionally coated with a film, using standard methods such as the use of a white concentrate, methylhydroxypropylcellulose, titanium dioxide, polyethylene glycol and polysorbate.

It is noted that in relation to this date the best method known by 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 (12)

1. Valaciclovir hydrochloride in an essentially anhydrous crystalline form, characterized in that it substantially includes the following configuration of the spacing d (in Ang ~ -roms): 10. 20 ± 0.08, 8.10 ± 0.06, 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ± 0.02.

2. The crystalline valaciclovir hydrochloride accng to claim 1, characterized in that it has a water content of hydration of not more than 3% w / w.

3. The crystalline valaciclovir hydrochloride accng to claim 2, characterized in that it has a water content of hydration of not more than 2% w / w.

4. The crystalline valaciclovir hydrochloride accng to claim 3, characterized in that it has a water content of hydration of not more than 1% w / w.

5. The crystalline valaciclovir hydrochloride, characterized in that it has substantially the same X-ray diffraction pattern as was shown in Figures 1 to 3.

6. The crystalline valaciclovir hydrochloride accng to any of the preceding claims, characterized in that it is used in medical therapy.

7. The use of valaciclovir hydrochloride accng to any of claims 1 to 5 in the preparation of a medicament for the treatment of a herpes viral infection.

8. A method for the treatment of viral herpes infection in a human being, characterized in that it comprises administering to the human patient, an effective anti-herpes viral amount of crystalline valaciclovir hydrochloride accng to any of claims 1 to 5.

9. A process for the production of valaciclovir hydrochloride in an anhydrous crystalline form that substantially includes the spaced d accng to claim 1, the process is characterized in that it comprises treating the vaiaciclcvir hydrochloride in an amount of 15% to 40% w / w of the lower alkoxy having 1 to 4 carbon atoms or of a lower ketone containing from 3 to 6 carbon atoms, which serves to convert an amount of the valacyclovir hydrochloride to the crystalline anhydrous form; and then isolate the anhydrous crystalline form.

10. "A process for the production of valaciclovir hydrochloride in an anhydrous crystalline form that substantially includes the spaced d accng to claim 1, the method is characterized in that it comprises the steps of: a) form valaciclovir in solution either in the free base or in the salt form; b) converting valaciclovir from the free base or the salt thereof to valaciclovir hydrochloride; c) isolate the valaciclovir hydrochloride from the solution and optionally remove the unbound solvent, leaving the valaciclovir hydrochloride in the substantially dry form; d) treating valaciclovir hydrochloride with 15% to 40% w / w of a lower alcohol having 1 to 4 carbon atoms or of a lower ketone containing from 3 to 6 carbon atoms used to convert an amount of the hydrochloride of valaciclovir optionally dried in the anhydrous crystalline form; and e) isolating the anhydrous crystalline form.

11. A process accng to claim 10, characterized in that the lower alcohol is ethanol or a solvent substantially composed of ethanol.

12. A process accng to claim 11, characterized in that the lower alcohol is ethanol or a solvent substantially composed of ethanol and is added in a range of about 17% by weight to about 40% by weight of the valaciclovir hydrochloride substantially dry.