FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"A METHOD OF MAKING VALACYCLOVIR HYDROCHLORIDE FORM"
TEVA PHARMACEUTICAL INDUSTRIES LTD., having a place of business at 5 Basel Street, P O Box 3190, Petah Tiqva 49131, Israel,
The following specification particularly describes the invention and the manner in which it is to be performed:

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CRYSTALLINE FORMS OF VALACYCLOVIR HYDRO CHLORIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the following U.S. Provisional Applications: No. 60/317,850, filed September 7,2001; No. 60/342,273, filed December 21,2001; No. 60/386,505, filed June 5,2002; and No. 60/403,838, filed August 14,2002.
FTELD OF THE INVENTION
The present invention relates to novel crystalline forms (polymorphs and pseudopolymorphs) of the antiviral compound valacyclovir hydrochloride, and methods for obtaining them.
BACKGROUND
Valacyclovir is an L-valyl ester prodrug of acyclovir. Acyclovir is an acyclic analog of a natural nucleoside which has been found to have high anti-viral activity. Acyclovir is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics 1193-1198 (9th ed. 1996).
Acyclovir is an acyclic guanine nucleoside analog that lacks a 3'-hydroxyl on the side chain. Acyclovir has the chemical name 6H-Purin-6-one, 2-amino-l,9-dihydro-9-[(2-hydroxyethoxy)methyl]. (CAS Registry No. 59277-89-3.) Acyclovir as the sodium 20 salt is currently marketed as ZOVIRAX®. The chemical structure of acyclovir is shown as Formula I.

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## STR( PCT7US02/28517


Formula I
)##
5 Valacyclovir has the chemical name 1-valme, 2-[(2-arnino-l,6-diliydro-6-oxo-9H-
purin-9-yl)methoxy] ethyl ester. (CAS Registry No. 124832-26-4.) Valacyclovir is currently marketed as VALTREX®. The chemical structure of valacyclovir is shown as Formula H

## STR(

S Pr-i

10 )##
Formula II
For oral administration, it is advantageous to administer valacyclovir rather than acyclovir because acyclovir is poorly absorbed from the gastrointestinal tract after oral
15 administration in both animals and humans. la contrast, valacyclovir is rapidly absorbed from the gastrointestinal tract after oral adrninistration. Moreover, valacyclovir is converted rapidly and virtually completely to acyclovir after oral adrninistration in healthy adults. The conversion of valacyclovir is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis.
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Acyclovir kills viruses by inhibiting viral DNA synthesis. Because acyclovir is a guanosine analog which lacks the 3'-hydroxy! on the side chain, it causes DNA chain termination during viral DNA replication. In virus infected cells, acyclovir is converted to the monophosphate derivative (acyclovir-MP) by a viral enzyme, thymidmine kinase. Acyclovir-MP is then phosphorylated to the diphosphate and triphosphate analogs by cellular enzyme. Incorporation of activated acyclovir into the primer strand during viral DNA replication, leads to chain termination, since without the 3' hydroxyl the DNA chain can not be extended. Since uninfected cells lack the viral enzyme thymidine kinase, acyclovir is selectively activated only in cells infected with viruses that code for the appropriate kinases.
U.S. Pat. No. 4,199,574 discloses the treatment of viral infections with acyclovir.
U.S. Pat. No. 4,957,924 (the '924 Patent") discloses amino acid esters of the purine nucleoside acyclovir, pharmaceutically acceptable salts thereof and their use in the treatment of herpes virus infections. Also disclosed are pharmaceutical formulations and processes for the preparation of such compounds. Valacyclovir and its salts, including the hydrochloride salt, are among the disclosed compounds.
The '924 patent further discloses a method for the preparation of valacyclovir by condensation of CBZ-Valine and acyclovir in Dimethylformamide (DMF) with catalytic amount of 4-dimethylaminopyridine (DMAP) and Dicyclohex3'lcarbodirmide (DCC) as a coupling reagent.
## STR(

)##

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U.S. Pat. No. 6,107,302, incorporated herein by reference, discloses an anhydrous crystalline form of valacyclovir hydrochloride and a process of preparation.
The discovery of a new crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. It is clearly advantageous when this repertoire is enlarged by the discovery of new crystalline forms of a useful compound. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G.M. Wall, Pharm Manuf. 3, 33 (1986); J.K. Haleblian and W. McCrone, J. Pharm. Set, 58, 911 (1969); and J.K. Haleblian, J. Pharm. Set, 64,1269 (1975), all of which are incorporated herein by reference.
The solid state physical properties of crystalline forms of a pharmaceutically useful hydrochloride can be influenced by controlling the conditions under which the hydrochloride salt is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular crystalline form of a substance. The crystalline form may give rise to thermal behavior different from that of the amorphous material or another crystalline form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis
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(TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some crystalline forms from others. A particular crystalline form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
5 BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 shows a representative X-ray diffraction pattern of valacyclovir hydrochloride in form I.
Fig. 2 shows a representative DTG thermogram of valacyclovir hydrochloride in
form I.

10 Fig. 3 shows a representativeX-ray diffraction pattern of valacyclovir
hydrochloride in form II.
Fig. 4 shows a representative DTG thermogram of valacyclovir hydrochloride in form II.
Fig. 5 shows a representative DTG thermogram of valacyclovir hydrochloride in 15 form IV.
Fig. 6 shows a representative X-ray diffraction pattern obtained when valacyclovir hydrochloride was incubated in controlled humidity cell having a relative humidity of 100% for 1 week to yield valacyclovir hydrochloride in form IV.
Fig. 7 shows a representative x-ray diffraction diagram for valacyclovir 20 hydrochloride in form V.
Fig. 8 shows representative differential thermal analysis and thermogravimetric thermograms for valacyclovir hydrochloride in form V.
Fig. 9 shows a representative X-ray diffraction pattern for valacyclovir hydrochloride in form VL
25 Fig. 10 shows a representative X-ray diffraction pattern for valacyclovir
hydrochloride in form VTI.
SUMMARY OF THE INVENTION
hi one aspect, the present invention relates to valacyclovir hydrochloride in crystalline forms I, n, TV, V, VI, and VTI as well as admixtures of two or more of these forms.
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In another aspect, the present invention relates to methods of making forms I, II, ]H, IV, V, VI and VII and mixtures thereof. The present invention also relates to pharmaceutical compositions containing valacyclovir hydrochloride in crystalline forms I, II, IV, V, VI, and VII as well as mixtures of two or more of these.
5 In one aspect, the present invention relates to valacyclovir hydrochloride in form I,
characterized by x-ray diffraction peaks(reflections) at about 3.7, 8.6,10.6,10.9,16.5, 24.0, and 27.2 ± 0.2 degrees two-theta.
In one aspect, the present invention relates to valacyclovir hydrochloride in form I, characterized by x-ray diffraction peaks(reflections) at about 3.7, 8.6,, 10.6,10.9, 16.5, 24.0, and 27.2 ± 0.2 degrees two-theta, and further characterized by x-ray diffraction peaks (reflections) at 9.5,13.3,20.1,21.4, and 26.7 degrees two theta.
In another aspect, the present invention also relates to valacyclovir hydrochloride in form I having the x-ray powder diffraction pattern substantially as shown in Fig. 1.
In another aspect, the present invention also relates to valacyclovir hydrochloride 15 in form I further characterized as having a weight loss of between about 6% and about 9% as measured by thermogravimetric analysis over the temperature range between about 25°C and about 140°C. This water content corresponds to the stochiometric amount of water in the sesquihydrate and is agreement with water contend determined by Karl-Fisher.
2O The present invention also relates to a pharmaceutical composition including
valacyclovir hydrochloride in form I.
In another aspect, the present invention also relates to valacyclovir hydrochloride in form H
The present invention also relates to valacyclovir hydrochloride in form It, characterized by x-ray diffraction peaks(reflections) at about 6.6, 11.5,17.2,19.0,21.5, 27.4 and 28.0 ± 0.2 degrees two-theta.
In another aspect, the present invention also relates to valacyclovir hydrochloride in form II, characterized by x-ray diffraction peaks(reflections) at about 6.6,11.5,17.2,
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19.0,21.5,27.4 and 28.0 ± 0.2 degrees two-theta, and further characterized by additional x-ray diffraction peaks (reflections) at 9.2,15.6, and 26.3 ± 0.2 degrees two-theta.
The present invention also relates to valacyclovir hydrochloride in form n, further characterized as having an endothermic peak at about 211°C through differential thermal analysis.
The present invention also relates to valacyclovir hydrochloride in form It having the X-ray powder diffraction pattern substantially as shown in Fig. 3.
The present invention also relates to a pharmaceutical composition including
valacyclovir hydrochloride form II.
10 In another aspect, the present invention relates to valacyclovir hydrochloride form
IV.
In yet another aspect, the present invention relates to valacyclovir hydrochloride form IV, characterized by x-ray diffraction peaks at about 3.6,10.7,15.1,26.9, and 28.1 ± 0.2 degrees two-theta.
In yet another aspect, the present invention relates to valacyclovir hydrochloride form IV, characterized by x-ray diffraction peaks at about 3.6, 10.7, 15.1, 26.9, and 28.1 ± 0.2 degrees two-theta, and further characterized by x-ray diffraction peaks (reflections) at 7.2, 8.7, 9.5,13.3,16.5,23.5, and 24.0 degrees two-theta.
In another aspect, the present invention relates to valacyclovir hydrochloride in form rV further characterized by additional x-ray diffraction reflections at about 7.2°, 8.6°, 9.5°, 13.3°, 15.2°, 27.3°, and 28.1° ± 0.2° two-theta.
The present invention also relates to valacyclovir hydrochloride form TV having the X-ray powder diffraction pattern substantially as shown in Fig. 6
In another aspect, the present invention relates to valacyclovir hydrochloride form 25 IV further characterized as having a weight loss of between about 9% and about 11% as measured by thernogravimetric analysis over the temperature range between about 25° C and about 170° C. This LOD value corresponds to the stoichiometric amount of water determined by the Karl-Fisher method.
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The present invention also relates to a pharmaceutical composition including valacyclovir hydrochloride form IV.
In one aspect, the present invention relates to valacyclovir hydrochloride in crystalline form IV.
5 In another aspect, the present invention also relates to valacyclovir hydrochloride
in form V having the X-ray powder diffraction pattern substantially as shown in Fig. 12.
In another aspect, the present invention relates to valacyclovir hydrochloride in form V having x-ray reflections (peaks) at about 6.7°, 15.7°, 16.2°, and 22.6°± 0.2° 29.
In another aspect, the present invention relates to valacyclovir hydrochloride in form V having additional x-ray reflections (peaks) at about 3.4°, 9.5°, 13.5°, 21.9°, 27.2°, and 28.6°± 0.2° 20.
In another aspect, the present invention relates to valacyclovir hydrochloride in form V further characterized as having a weight loss of between about 5% and about 7% as measured by thermogravimetric analysis over the temperature range between about 25 15 °C and about 130 °C.
In another aspect, the present invention relates to valacyclovir hydrochloride in form V further characterized by a broad endothermic peak at about 95 °C and a sharp endothermic peak at about 180 °C as exhibited by differential theimogravimetric analysis.
The present invention also relates to pharmaceutical compositions including 20 valacyclovir hydrochloride in form V.
In yet another aspect, the present invention relates to valacyclovir hydrochloride in crystalline in form VI.
In another aspect, the present invention relates to valacyclovir hydrochloride in form VI characterized by x-ray diffraction peaks (reflections) at about 6.2°, 9.2°, 12.1°, 25 20.2° and 25.7° ±0.2° 29.
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In another aspect, the present invention relates to valacyclovir hydrochloride in form VI characterized by the x-ray powder diffraction pattern substantially as shown in Figure 14.
The present invention also relates to pharmaceutical compositions including 5 valacyclovir hydrochloride in form VI.
In another aspect, the present invention relates to valacyclovir hydrochloride in crystalline form VII.
In still another aspect, the present invention relates to valacyclovir hydrochloride
\ in form VII characterized by an X-ray diffraction pattern having peaks (reflections) at
10 about 3.5°, 10.3°, 13.6°, 26.2° and 28.1° 26.
In still another aspect, the present invention relates to valacyclovir hydrochloride in form VII characterized by the x-ray powder diffraction pattern substantially as shown in Figure 15.
The present invention also relates to pharmaceutical compositions including 15 valacyclovir hydrochloride in form VII.
In another aspect, the present invention also relates to a process for preparing valacyclovir hydrochloride form I, including the step of suspending valacyclovir hydrochloride as a slurry in a slurry solvent, wherein the slurry solvent is selected from the group that is ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylene chloride, t-20 butyl methyl ether, and tetrahydrofurane.
In another aspect, the present invention also relates to a process for preparing valacyclovir hydrochloride in form I, including the steps of suspending valacyclovir hydrochloride as a slurry in a slurry solvent, wherein the slurry solvent is selected from the group that is ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylene chloride, t-25 butyl methyl ether, and tetrahydrofurane; isolating valacyclovir hydrochloride in form I from the slurry; and drying valacyclovir form I at a temperature between about 20°C and about 70°C.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form II including the step of slurrying, at ambient temperature,
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vafacyclovir hydrochloride in a slurry solvent selected from isopropyl alcohol, 1-butanol, or ethanol.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form II including the step of slurrying valacyclovir hydrochloride in toluene and, optionally, isolating valacyclovir hydrochloride in form II from the slurry and drying the valacyclovir hydrochloride form II, preferably at a temperature of about 60°C. Optionally, drying is at a pressure less than about 500 mm Hg and a temperature of about 50°C.
In yet another aspect, the present invention relates to a reflux slurry method of making
valacyclovir hydrochloride in form It including the steps of slurrying valacyclovir in a
slurry solvent selected from acetonitrille, methyl ethyl ketone, ethyl acetate, acetone, and
toluene, heating the slurry to reflux, refluxing the resulting mixture, and isolating
valacyclovir hydrochloride in form II from the mixture.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form II including the steps of slurrying valacyclovir hydrochloride in toluene; heating the slurry to reflux; adding methanol to the slurry; refluxing the resulting mixture; and isolating valacyclovir hydrochloride in form II from the mixture.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form HI including the step of incubating valacyclovir hydrochloride in an atmosphere saturated with vapors of at least one of the following incubating solvents: isopropanol, ethanol, butanol, acetone, ethyl acetate, tetrahydrofurane, acetonitrile, methanol, and water. The valacyclovir hydrochloride can be in solid form or in solution in the incubating solvent.
In another aspect, the present invention relates to a method of making valacyclovir in form IV including the step of incubating valacyclovir hydrochloride in an atmosphere having a relative humidity of about 100%.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form V including the step of mixing a solution of valacyclovir hydrochloride in water with a lower aliphatic alcohol.
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In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form V including the step of mixing a solution of valacyclovir hydrochloride in water with iso-propanol.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form VI including the step of mixing a solution of valacyclovir hydrochloride in a first solvent including water and an aliphatic monocarboxylic acid with a second solvent including a water-miscible ketone, particularly acetone, to form a suspension.
In another aspect, the present invention relates to a method of making valacyclovir ) hydrochloride in form VI including the step of mixing a solution of valacyclovir
hydrochloride in a first solvent including between about 30 % and about 60% by volume of water, the remainder an aliphatic monocarboxylic acid, with a second solvent including a water-miscible ketone in an amount that is about 2 to about 5 times the volume of the first solvent.
15 In another aspect, the present invention relates to a method of making valacyclovir
hydrochloride in form VI including the step of filtering the solution of valacyclovir hydrochloride in a first solvent including water and an ahphatic monocarboxylic acid; then mixing die solution with a second solvent including a water-miscible ketone, preferably acetone, to form a suspension; and optionally, agitating the suspension at a temperature
20 less than about -10° C and isolating valacycvlovir hydrochloride in form VI from the suspension.
In another aspect, the present invention relates to a method of making valacyclovir hydrochloride in form VII including the step of mixing a solution of valacyclovir hydrochloride in a first solvent that is essentially water with a second solvent that includes 25 a water-miscible ketone, preferably acetone, to form a suspension; and optionally further including the steps of agitating the suspension at a temperature less than about 10° C and isolating valacyclovir hydrochloride in form VII from the suspension. A method of making valacyclovir hydrochloride in form I including the step of heating valacyclovir hydrochloride for about 2 hours at a temperature between about 110° C and about 130° C.
30 In another aspect, the present invention relates to a method of making valacyclovir
hydrochloride in form I including the steps of dissolving valacyclovir hydrochloride in a solvent, and evaporating the solution at a reduced pressure. Preferably, the solvent is a
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polar organic solvent having 4 or fewer carbon atoms. Most preferably, the solvent is an alcohol, preferably methanol.
In another aspect, the present invention relates to a pharmaceutical composition including any one of valacyclovir hydrochloride in form I, II, IV, V, VI or VII.
5 In another aspect, the present invention relates to a pharmaceutical composition
including any mixture of two or more of valacyclovir hydrochloride in form I, II, IV, V, VI or VII.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides valacyclovir hydrochloride in new crystalline 10 forms I, II, IV, V, VI, and VII as well as admixtures of two or more of these forms. The present invention also provides methods for preparing valacyclovir hydrochloride in crystalline forms I, II, HI, TV, V, VI, and VII as well as admixtures of two or more of these forms.
The present invention further relates to the solid state physical properties of these 15 crystalline forms of valacyclovir hydrochloride as prepared by any of the methods of the present invention, as well as by other methods known to those skilled in the art.
As used herein, unless the context requires otherwise, the term "valacyclovir
hydrochloride" includes anhydrous forms, hydrates, solvates, and all crystalline forms
, (both polymorphs and pseudopolymoiphs), of valacyclovir hydrochloride. As used herein,
20 the term polymorphs is used broadly to include both polymorphs and pseudopolymorphs, i.e., all crystalline forms.
As used herein in connection with a measured quantity, the term "about refers to that variation in the measured quantity as would be expected by the skilled artisan performing the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.
For the purposes of this specification, ambient or room temperature is from about 20°C to about 25°C, elevated temperature means above about 38°C, and cold temperature means below about -10°C.
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All powder x-ray diffraction patterns were obtained by methods known in the art using a Scintag X'TRA X-ray powder diffractometer, equipped with a solid state Si(Li) detector thermoelectrically cooled, at scanning speed of 3° min-1. The scanning range was 2-40 degrees two-theta. Copper radiation of “ = 1.5418 ° was used. The term x-ray diffraction "peaks" as used herein refers to x-ray diffraction "reflections" measured using an x-ray powder diffractometer. "Wet" samples (i.e. samples not dried) was analyzed as is. Dry samples were gently ground before analysis.
The differential thermal analysis ("DTA") and thermogravimetric analysis ("TGA") curves presented herein were obtained by methods known in the art using a DTG Shimadzu model DTG-50 (combined TGA and DTA). The weight of the samples was about 9 to about 13 mg. The samples were scanned up to about 300°C at a rate of 10°C/min. Sample chambers were purged with nitrogen gas at a flow rate of 20 ml/min. Uncovered standard alumina crucibles were used.
Thermogravimetric analysis (TGA) is a measure of the thermally induced weight loss of a material. Thermogravimetric analysis (TGA) is a thermal analysis technique well known in the art that detects and measures events that have associated with them a loss of mass, e.g. loss of water of hydration, as a function of temperature.
DTA denotes differential thermal analysis, a technique well known in the art, that detects and measures thermal events in a sample, e.g. phase transitions, in which heat is either absorbed (endothermic) or liberated (exothermic).
Karl Fisher analysis, which is well known in the art, is also used to determine the quantity of water in a sample.
The term "water content" refers to the content of water based upon the Loss on Drying method (the "LOD" method) as described in U.S. Pharmacopeia Forum, Vol. 24, No. 1, p. 5438 (Jan — Feb 1998), the Karl Fisher assay for determining water content or thermogravimetric analysis (TGA). The term "equivalents of water" means molar equivalents of water. All percentages referenced herein are by weight unless otherwise indicated.
Those skilled in the art will also understand that the term "anhydrous" when used in reference to valacyclovir hydrochloride describes valacyclovir hydrochloride which is substantially free of water. Those skilled in the art will appreciate that the term "hydrate"
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When used in reference to valacyclovir hydrochloride describes a crystalline material having a water content of about 6 - 10 % w/w.
When used in describing purity, percent refers to area percent determined by high-pressure liquid chromatography (HPLC), a method well-known to those skilled in the art, and is calculated according to the equation:
% impuruty i = 100 x (area under peak z) / (S area of all peaks).
In one embodiment, the present invention provides valacyclovir hydrochloride in
form I ("Form I"). '
)
Valacyclovir hydrochloride in form I is characterized by an x-ray diffraction pattern with peaks (reflections) at about 3.7, 8.6,10.6, a0.9,13.3,16.5,24.0, and 27.2 ±0.2
degrees two-theta. Figure 1 shows a representative x-ray powder diffraction pattern of
valacyclovir hydrochloride in form I.
Valacyclovir hydrochloride in form I is also characterized by the thermal profile measured using the DTG-50 as discussed above, which provides both TGA and DTA 15 thermograms as shown in Fig. 2. The DTA thermogram shows a broad endotherm below 125°C. The weight loss curve also shows a weight loss step in this temperature range, with a measured loss on drying value from about 6% to about 9% by weight. This LOD value corresponds to the stoichiometric amount of water of valacyclovir hydrochloride sesquihydrate and agrees with the water content determined by the Karl-Fisher method.
20 In another embodiment, the present invention provides valacyclovir hydrochloride
in form H ("Form H").
Valacyclovir hydrochloride in form II is characterized by an x-ray diffraction pattern with peaks (reflections) at about 6.6,11.5,17.3,19.0,21.5,26.3,27.4 and 28.0 ± 0.2 degrees two theta. Fig. 3 shows a representative x-ray powder diffraction pattern of valacyclovir hydrochloride in form II.
Valacyclovir hydrochloride in form II can also be characterized by differential thermal analysis (DTA), as shown in Fig. 4, which shows an endothermic peak at 211°C followed by an exothermic peak.
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Valacyclovir hydrochloride in form HI ("Form III") is the prior art anhydrous form of valacyclovir hydrochloride disclosed in US Patent No. 6,107,302.
In one embodiment, the present invention provides a method for preparing valacyclovir hydrochloride in form HI.
5 In another embodiment, the present invention provides valacyclovir hydrochloride
in form IV ("Form IV").
Valacyclovir hydrochloride in form IV is characterized by an x-ray diffraction
pattern with peaks (reflections) at about 3.6,10.7,15.1,26.9, and 28.1 ± 0.2 degrees two-
) theta. Fig. @@ shows a representative x-ray diffraction pattern for valacyclovir
10 hydrochloride in form IV.
Valacyclovir hydrochloride in form IV can be further characterized by the thermal thermal analysis using the DTG-50 as discussed above, which provides both TGA and DTA thermograms as shown in Fig. 5. The DTA thermogram shows two broad endotherrnic peaks at about 45 °C and 100°C. The weight loss curve shows two weight loss steps in the temperature range of up to about 130°C. The loss on drying (LOD) value in this temperature range is about 9.7 %. This corresponds to the stoichiometric amount of water of valacyclovir hydrochloride dihydrate and agrees with the water content determined by the Karl-Fisher method.
Form IV can include higher amounts of solvents, up to about 15%.
i
20 In still another embodiment, the present invention provides valacyclovir hydrochloride
in form V.
Valacyclovir hydrochloride in form V is characterized by x-ray reflections (peaks) at about 6.7°, 15.7°, 16.2°, and 22.6° ± 0.2 degrees two-theta.
Valacyclovir hydrochloride in form V of the present invention can be further characterized by additional x-ray reflections (peaks) at about 3.4°, 9.5°, 13.5°, 21.9°, 27.2°, and 28.6°± 0.2° two-theta. Figure 12 shows a representative x-ray powder diffraction pattern of valacyclovir hydrochloride in form V.
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Valacyclovir hydrochloride in form V can be further characterized by DTA and TGA measurements as shown in Figure 13. DTA thermograms of valacyclovir hydrochloride in form V of the present invention exhibit a broad endothermic peak at about 95 °C and a sharp endothermic peak at about 180 °C. The weight loss curve (TGA) shows a weight loss of between about 5% and about 7% over the temperature range between about 25 °C and about 130 °C.
In another embodiment, the present invention provides valacyclovir hydrochloride in form VI ("Form VI").
Valacyclovir hydrochloride in form VI is characterized by X-ray diffraction ) 10 reflections (peaks) at about 6.2°, 9.2°, 12.1°, 20.2° and 25.7°± 0.2° 20. Figure 14 shows a representative x-ray powder diffraction pattern for valacyclovir hydrochloride in form VI.
In yet another embodiment, the present invention provides valacyclovir hydrochloride in form VII ("Form VH").
Valacyclovir hydrochloride in form VII is characterized by x-ray reflections 15 (peaks) at about 3.5°, 10.3°, 13.6°, 26.2° and 28.1° ± 0.2° 20. Figure 15 shows a
representative x-ray powder diffraction pattern for valacyclovir hydrochloride in form VII.
The novel crystalline forms (polymorphs and pseudopolymorphs) of valacyclovir hydrochloride of the present invention can be prepared by any one or more of the methods described below, each of which represents an embodiment of the present invention. Three ho methods used in particular embodiments are: (1) the slurry method, also known as the trituration method; (2) the vapor incubation method; and (3) the precipitation method. Also provided are thermal and evaporative methods for making valacyclovir hydrochloride in form I.
In particular embodiments, the crystalline forms of valacyclovir hydrochloride of the present invention can be made by a slurry method that includes the step of suspending, or "slurrying", a quantity of valacyclovir hydrochloride in a slurry solvent, preferably with the aid of mechanical agitation.
Examples of procedures for forming polymorphs by the slurry method are provided in examples 1 to 21. The amount of slurry solvent can vary between about 5 mL and about 15 mL, preferably between about 8 mL and about 12 mL, most preferably about
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10 mL per gram of valacyclovir hydrochloride. The slurry is agitated for a time sufficient to achieve the desired transformation. Agitation may be provided by any means known to those skilled in the art, for example by using a magnetic stirrer or a propeller-type stirrer inserted into the solution. It was surprisingly found that polymorph formation by the slurry method can be more efficient when a magnetic stirrer rather than a propeller was used to promote stirring.
The extent of transformation during agitation can be monitored by, for example, removing an aliquot of the slurry, separating the solid, and analyzing the crystal form of the solid by, for example, x-ray diffraction.
Valacyclovir hydrochloride in the resulting crystalline form can be isolated from the slurry by any means known in the art. For example, filtration (gravity or suction) or centrifugation may be used, to mention just two.
If desired, or if required to make a particular polymorph, the product isolated from the slurry method can be dried at atmospheric pressure, or it can be dried at reduced pressure.
In other embodiments, the crystal forms of the present invention can be made by a vapor incubation method. In the vapor incubation method, valacyclovir hydrochloride is exposed to an atmosphere saturated or nearly saturated with vapors of an incubating solvent. Valacyclovir hydrochloride can be exposed as solid particles, preferably in a thin layer to maximize the surface exposed to vapors of the incubating solvent, or it can be exposed as its solution in the incubating solvent Vapor incubation can be performed by placing a quantity of a solid form of valacyclovir hydrochloride in a small open container or by incubating valacyclovir hydrochloride in a solvent atmosphere in a closed container.
Preferably, the sample is incubated for a time ranging from about 7 to about 32 days. When the incubating solvent is water, the degree of chamber humidity may be regulated using salts or salt solutions such as potassium sulphate, zinc nitrate, potassium acetate, ammonium sulphate, as is known in the art.
If desired, of if required to make a particular polymorph, product from the incubation method can be dried at atmospheric pressure, or it can be dried at reduced pressure.
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Examples of procedures for preparing crystalline forms of valacyclovir hydrochloride by the vapor incubation method are provided in examples 22-27.
In still other embodiments, the crystal forms of the present invention can be made by a precipitation method that includes the step of mixing, with mechanical agitation, a solution of valacyclovir hydrochloride in a first solvent with a second solvent to form a suspension. Preferably, valacyclovir hydrochloride is practically insoluble in the second solvent.
Examples of procedures for preparing crystalline forms of valacyclovir hydrochloride by the precipitation method are provided in examples 28 to 32.
The concentration of valacyclovir hydrochloride in first solvent can vary from between about 30 to about 65 %. The ratio of the volume of second solvent to solution can vary between about 3 :1 to about 15:1, relative to the volume of solution in first solvent
Mechanical agitation can be provided by any means known in the art, for example magnetic stirrers or paddle-, propeller- or turbine-type stirrers, to mention just a few. The skilled artisan will know to select the means of agitation depending on, among other things, the size and geometry of the vessel being used and the viscosity of the solution and suspension.
In preferred embodiments that incorporate the precipitation method, the method includes the step of agitating the suspension for about 2 to about 24 hours at a temperature less than about-10° C.
Valacyclovir hydrochloride in the resulting crystal form can be isolated from the suspension by any means known in the art. For example, filtration (gravity or suction) or centrifugation can be used, to mention just two. After isolation, the valacyclovir hydrochloride in the resulting crystal form can be dried at atmospheric pressure or at
reduced pressure (vacuum), both methods of which are known in the art.
i
It will be understood by those of skill in the art that other methods may also be used to produce the crystalline forms disclosed herein.
In one embodiment, the present invention provides a thermal method for making valacyclovir hydrochloride in form I including the step of heating valacyclovir
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hydrochloride for about 1 to about 3 hours, preferably about 2 hr, at a temperature between about 30° C and about 60° C, preferably 40° C. Preferably, the material is dried under vacuum. The product so obtained is valacyclovir hydrochloride in form I according to x-ray diffraction analysis.
In another embodiment, the present method provides an evaporative method for making valacyclovir hydrochloride in form I. In the evaporative method, valacyclovir hydrochloride is dissolved in an amount of solvent (about 200 mL to about 300 mL, preferably about 250 mL, solvent per gram of valacyclovir hydrochloride) at 40° C. The solvent is evaporated, preferably at reduced pressure, to yield valacyclovir hydrochloride in form I. Polar organic solvents, especially alcohols, having 4 or fewer carbon atoms are preferred for use in the evaporation method. Methanol is a particularly preferred solvent for use in this method.
ha yet another embodiment, the present invention provides a slurry method for making valacyclovir hydrochloride in form I, including the step of suspending valacyclovir hydrochloride as a slurry in a sluiry solvent, and optionally, the further steps of isolating valacyclovir hydrochloride in form I from the slurry and drying at a temperature between about 50°C and about 70°C. The slurry solvent for preparing valacyclovir hydrochloride in form I is a non-polar organic solvent, preferably selected from ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylene chloride, t-butyl methyl ether, and tetrahydrofurane.
In another embodiment, the present invention provides a slurry method for making valacyclovir hydrochloride in form II, including the step of suspending valacyclovir hydrochloride as a slurry in a slurry solvent selected from isopropyl alcohol, 1-butanol, acetonitrile, methyl ethyl ketone, ethyl acetate, ethanol, acetone and toluene.
The slurry can be agitated with any stirrer known in the art, preferably a propeller-type stirrer, and most preferably, a magnetic stirrer. The step of suspending valacyclovir hydrochloride as a slurry is performed for about 20 to about 28, preferably about 24 hours.
In another embodiment, the present invention provides a slurry method of making valacyclovir hydrochloride in form II including the steps of suspending valacyclovir hydrochloride as a slurry in a slurry solvent at reflux; adding methanol to the slurry; refluxing the resultant mixture; and isolating valacyclovir hydrochloride in form II from the mixture.
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In another embodiment, the present invention provides a slurry method for making valacyclovir hydrochloride form II, including the steps of: suspending valacyclovir hydrochloride as a slurry in a toluene at reflux; adding methanol to the slurry; further refluxing the resulting slurry in mixed solvents; and isolating valacyclovir hydrochloride in form II from the resulting slurry in mixed solvents.
Valacyclovir hydrochloride in form II can be isolated from the slurry by cooling the slurry to room temperature and collecting the crystals by any means known in the art.
In a particular embodiment, isolated crystals are dried under vacuum, i.e. at a pressure less than abut 500 mm Hg at 50 °C. Alternatively, the step of drying the crystals is performed at atmospheric pressure at 60 °C. )

In another embodiment, the present invention provides a method for making valacyclovir hydrochloride form IV, including the steps of incubating valacyclovir hydrochloride in an atmosphere saturated with vapors of at least one of the following incubating solvents: isopropanol, ethanol, butanol, acetone, ethyl acetate, tetrahydrofurane, acetonitrile, methanol, and water. The valacyclovir hydrochloride can be incubated as a solid or as a solution. Acetonitrile is a preferred incubating solvent when valacyclovir hydrochloride in solid form is used.
In a particular embodiment of the vapor incubation method, valacyclovir hydrochloride is dissolved in hot methanol and incubated in an atmosphere saturated with vapors of an incubating solvent in a closed container for from about 25 to about 40 days, preferably 32 days. The incubating solvent is preferably selected from acetone, ethyl acetate, tetrahydrofuran, ethanol, or butanol.
In another particular preferred embodiment, the present invention provides a process for preparing valacyclovir hydrochloride in form IV, including the steps of incubating valacyclovir hydrochloride in form II in an atmosphere saturated with water at 100% humidity.
In another embodiment, the present invention provides a method for making valacyclovir hydrochloride in forms I and IV by the precipitation method. Valacyclovir hydrochloride is dissolved in a first solvent, preferably about 6 mL first solvent per gram of valacyclovir hydrochloride, at about 20° C to about 30° C, preferably about 25° C. The solution in first solvent is mixed with a second solvent, in a volume amount about 10 to
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about 30, preferably about 17 times the volume of first solvent. The resulting suspension is stirred for aboutl hour and filtered to recover precipitate wet cake. Optionally, the precipitate wet cake is dried in vacuo at 40° C.
Water is the preferred first solvent. Polar organic solvents, protic or aprotic, are useful as second solvents. Preferred second solvents are acetonitrile, butanol, and acetone. Optionally, the second solvent can be used to form the initial solution and precipitation of the polymorph effected by addition of first solvent.
In another embodiment, the present invention provides a method of making valacyclovir hydrochloride in form V by the precipitation method, for example, by mixing a solution of valacyclovir hydrochloride in a first solvent with a second solvent that is an alcohol, preferably isopropanol.
The solution is in a first solvent that includes water and, optionally, a water-miscible organic solvent such as acetic acid, a water-miscible ketone, or, preferably, an alcohol. When a ketone is used, acetone is the preferred ketone. When alcohol is used, isopropanol is the preferred alcohol. Preferably, water is the major constituent of the solvent. Most preferably, the first solvent is water.
Preferably, the solution in the first solvent contains one part by weight valacyclovir hydrochloride and about 2 to about 6 parts by weight solvent. The solution can be made by, for example, dissolving the desired amount of valacyclovir hydrochloride in about 2 to about 6 parts by weight solvent. The valacyclovir hydrochloride can be made by any means known in the art, or it can be generated in situ from t-butoxycarbonyl valacyclovir (t-BOC Val), in which the nitrogen of the valine residue attached to the acyclovir moiety bears a butoxycarbonyl group.
When valacyclovir hydrochloride is generated in situ in a preferred embodiment, about 3 to about 7, preferably about 5, equivalents of hydrogen chloride, dissolved in a suitable vehicle, are added, preferably slowly to maintain temperature control, to a suspension of a protected valacyclovir (e.g., t-BOC valacyclovir) in a suitable solvent mentioned above. The vehicle can be any of those solvents mentioned above. Preferably, the vehicle and solvent are both water.
After addition of the hydrogen chloride, the mixture is stirred at a temperature below about 40° C, preferably at about 20° to 25° C, until the mixture essentially becomes
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a solution that can be roily or turbid. The mixture is then cooled to a temperature below about 10° C, preferably at about 0° C, and mixed with an alcohol, preferably isopropanol (20 to 30 volumes based on the volume of solvent used) to form a suspension. Preferably, the suspension is stirred for at least about one-half hour at this temperature. The suspension can be stirred at a temperature below about 4° C for a period of time, for example about 8 to about 18 hours.
Valacyclovir hydrochloride in form V can be isolated from the suspension by any means known in the art. For example, isolation can be by filtration (gravity or suction) or by centrifugation, to mention just two.
Typically, valacyclovir hydrochloride in form V prepared as described above will have a chemical purity of at least about 97%.
hi another embodiment, the present invention also provides a method of making valacyclovir hydrochloride in form VI by the precipitation method. Valacyclovir hydrochloride is dissolved in a first solvent including an aliphatic monocarboxylic acid and water. The solution is optionally filtered and the filtrate then combined with a second solvent that is a water-miscible ketone to form a suspension which is then cooled. Aliphatic monocarboxylic acids have the formula RCO2H wherein R is a linear or branched alkyl group having 1 to 6 carbon atoms. The preferred aliphatic monocarboxylic acid is acetic acid, and the preferred water-miscible ketone is acetone.
It is preferred to slowly combine the filtered solution in the first solvent (filtrate_ and the second solvent. Slowly combining means adding small amounts of filtrate, preferably dropwise, over a period of time, preferably from one-half hour to 3 three hours. It is especially preferred to add the filtrate dropwise over about an hour.
Valacyclovir hydrochloride in form VI can be recovered from the suspension by any means known in the art; for example, isolation can be by filtration (gravity or suction) or by centrifugation, to mention just two.
In another embodiment, the present invention provides a method of making valacyclovir hydrochloride in form VI by the precitation method. For example, BOC-valacyclovir is dissolved in acetic acid and mixed with hydrochloric acid and water. The solution is then filtered and the filtrate added dropwise to acetone to form a suspension which is then cooled.
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It is preferred to add one part by weight BOC-valacyclovir to about 2-5, preferably about 3, parts by weight of acetic acid. The mixture is stirred at an elevated temperature (over 38°C), preferably about 50°C, to dissolve the solids and subsequently cooled to ambient or room temperature, around 25°C. The mixture is maintained under an atmosphere of inert gas, preferably argon. A mixture of about 1 part hydrochloric acid to about 1-4, preferably 2, parts by weight water is then added dropwise over about 1 hour to the mixture of valacylovir and acetic acid.
After being stirred at ambient temperature for about 1 to 4 hours, preferably about 3 hours, the solution is filtered and the resultant filtrate is added over a period of time, preferably about 1 hour, to an amount of acetone that is about 2 to 5 times the volume of filtrate. The suspension is then stirred first for about 1 to 4 hours, preferably 2 hours, at ambient temperature and then for a longer time, 12 to 18 hours, preferably 14 hours, at a cold temperature below -10°C, preferably -15°C.
Typically, valacyclovir hydrochloride in form VI prepared as described above will have a chemical purity of at least about 98% purity.
In another embodiment, the present invention also provides a method of making valacyclovir hydrochloride in form VTI by the precipitation method, including the steps of: dissolving valacyclovir HC1 in first solvent that is water, filtering the solution, combining the filtered solution with a second solvent that is a water-miscible ketone to obtain a suspension, and then cooling and isolating valacyclovir hydrochloride in form VII. Acetone is the preferred water-miscible ketone.
Valacyclovir hydrochloride in form VII can be isolated from the suspension by any means known in the art. For example, isolation can be by filtration (gravity or suction) or by centrifugation, to mention just two.
Typically, one part by weight valacyclovir hydrochloride is dissolved with about 3-5, preferably about 4, parts by weight of water. The solution is stirred at an elevated temperature above about 38°C, preferably about 40°C, to dissolve the solids. The solids are then filtered. The resultant filtrate is added to an amount of a water-miscible ketone, preferably acetone, equal to about 2 to 6 times the volume of filtrate to form a suspension. The suspension is then stirred first for about 1 to about 4 hours, preferably 2 hours, at a temperature between about 20 and 25°C, preferably about 20°C, and then for a longer
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trail, about 10 to 18 hours, preferably about 12 hours, at a cold temperature below about -10°C, preferably-15°C.
Typically, valacyclovir hydrochloride in form VTI prepared as described above has a chemical purity of about 99%.
5 In still another embodiment, the present invention provides a method for making
valacyclovir hydrochloride monohydrate including the steps of contacting a solution of valacyclovir hydrochloride in water with about two to about four times the volume thereof of iso-propanol to form a suspension, stirring the suspension for a stirring period at a temperature below about -10°C, isolating the solid, and drying the solid at reduced
10 pressure to constant weight. The contacting is preferably by mixing with mechanical
\ agitation.
Preferably, the solution and IPA are contacted at a temperature between about 30°C and about 50°C, preferably at about 40°C. Preferably the temperature during the stirring period is about -15°C. The solid can be isolated from the suspension by any means known in the art, for example filtration.
Methods of use, Formulations, dosages
Valacyclovir hydrochloride may be formulated into a variety of pharmaceutical compositions and dosage forms that are useful in treating patients afflicted with viral infections, particularly infections caused by the herpes group of viruses.
2O In one embodiment, the present invention relates to pharmaceutical compositions
including valacyclovir hydrochloride in at least one of forms I, II, IV, V, VI or VII. In addition to the active ingredient(s), valacyclovir hydrochloride pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes.
25 Diluents increase the bulk of a solid pharmaceutical composition and may make a
pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVTCEL®, microfine cellulose, lactose, starch, pregelitrnized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
30 phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,
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magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form like a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g. -METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch.
Glidants can be added to improve the flow properties of non-compacted solid compositions and improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl famarate, stearic acid, talc and zinc stearate.
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Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vamllin, menthol, citric acid, fumaric acid ethyl maltol, and tartaric acid.
Compositions may also be colored using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. An especially preferred dosage form of the present invention is a tablet.
Tablets, capsules, lozenges and other unit dosage forms preferably contain modafinil in a dosage level of from about 50 to about 300 mg, more preferably from about 100 mg to about 200 mg.
The currently marketed form of valacyclovir (VALTREX®) contains valacyclovir hydrochloride equivalent to 500 mg valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide crospovidone, ED&C Blue No. 2 Lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystamxie cellulose polyethylene glycol, polysorbate 80, povidone and titanium dioxide.
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The function and advantage of these and other embodiments of the present invention will be more fully understood from the examples below. The following examples demonstrate the preparation of various crystalline forms of valacyclovir hydrochloride by the slurry method (examples 1 to 21), the vapor incubation method (examples 22 to 27), and the precipitation method (examples 28 to 32). Preparation of form I by the heating and evaporative method are also illustrated in examples 33 and 34 respectively. These examples are intended to illustrate the benefits of the present invention, but are not intended to limit the scope of the invention.
EXAMPLES
Preparation of crystalline forms of valacyclovir hydrochloride by the slurry method:
Example 1
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in ethyl acetate (10 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
Example 2
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in acetone (10 mL) for 24 hours. The mixture was filtered and the isolated sohd was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
Example 3
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in methyl ethyl ketone (MEK) (15 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
Example 4
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in dioxane (15 mL) for 24 hours. The mixture was filtered and the isolated sohd was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
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Example 5
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in methylene chloride (15 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
5 Example 6
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in t-butyl methyl ether (15 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
, Example 7
10 Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in
t-butyl methyl ether (20 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
Example 8
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in tetrahydiofurane (THF) (20 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form I.
Example 9
Valacyclovir hydrochloride (1 g) was suspended in slurry with a magnetical stirrer at ambient temperature in isopropyl alcohol (10 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 10
Valacyclovir hydrochloride (1 g) was suspended in slurry with a mechanical stirrer at ambient temperature in Isopropyl alcohol (15 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir -hydrochloride form II.
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Example 11
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in 1-butanol (10 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
5 Example 12
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in 1-butanol (20 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
) Example 13
10 Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in
acetonitrile (25 mL) for 24 hours. The mixture was filtered and the isolated sohd was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 14
Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in methyl ethyl ketone (20 mL) for 22 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 15
Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in ethyl acetate (20 mL) for 22 hours. The rnixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 16
Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature in ethanol absolute (15 mL) for 18 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
25 Example 17
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Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in Isopropyl alcohol (15 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 18
5 Valacyclovir hydrochloride (1 g) was suspended in slurry at ambient temperature
in acetonitrile (20 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form n.
Example 19
, Valacyclovir hydrochloride (1 g) was suspended in slurry at reflux temperature in
10 acetone (11 mL) for 24 hours. The mixture was filtered and the isolated solid was dried at 60°C for 24 hours to give valacyclovir hydrochloride form II.
Example 20
Valacyclovir hydrochloride (5 g) was placed in a three neck flask equipped with a Dean-Stark Trap. Toluene (40 mL) was then added and the slurry was heated to reflux temperature. At reflux temperature, toluene (160 mL) and methanol (20 mL) were added. Thirty mL of the solvent were distilled and more methanol added (30 mL). The reaction mixture was refluxed for 45 minutes and the slurry was cooled to ambient temperature, filtered under reduced pressure and dried according to 2 different procedures: (1) by vacuum oven at 50°C for 24 hours; and, (2) atmospheric oven at 60°C for 24 hours. Both ; samples were valacyclovir hydrochloride form H.
Example 21
General procedure: two grams of valacyclovir hydrochloride were stirred in the desired refluxing solvent (200 mL) for 1 hr. The slurry was cooled to room temperature (ca. 25° C) over a period of about 1 hr. The suspension so obtained was filtered to obtain wet cake. A portion of the wet cake was analysed by x-ray diffraction to determine the polymorphic form. The wet cake was dried in vacuo at 40° C. The water content and polymorphic (crystal) form of the product after the drying step were determined.
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The general procedure was repeated with various solvents. The table below lists the polymorph and moisture content obtained with the various solvents, with (d) and without (w) drying.

Exp. Solvent X-Ray Results
137-01 w IPA IV + III
137-02 d 138-01w Iv + II
EtOH IV
138-02 d I
139-01 w Acetone IV
139-02 d I
140-01 w THF rv
140-02 d i
141-01w EtOH/H20 (100:1) IV»»III
141-02 d I
142-01w EtOH/H20 (100:2) IV
142-02 d 149-01d I
149-01 d EtOH/H20 (100:2) IV
143-01w EtOH/H20 (100:5) IV»»III
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* 150-01 d EtOH/H20 (100:5) I
144-01 w IPA/H20 (100:3) I
144-02 d I+ 11
145-01w IPA/H20 (100:8) IV
145-02 d I
148-01 w BuOH III
148-02 d II
155-01w Dioxane I
155-02 d I
161-01-w MEK IV
161-02-d I
Preparation of crystalline forms of valacyclovir hydrochloride by the vapor incubation method:
Example 22
Valacyclovir hydrochloride dry was incubated in a solvent atmosphere of acetonitrile for 1 week. The wet sample was then analyzed by powder X-ray crystallography and shown to be valacyclovir hydrochloride form II.
Example 23
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Valacyclovir hydrochloride form I was incubated in controlled humidity cell having a relative humidity of 100% for 1 week to yield valacyclovir hydrochloride form IV dihydrate.
Example 24
5 Valacyclovir hydrochloride was dissolved in a minimum of hot methanol. The
methanol solution was incubated in solvent saturated atmosphere for 32 days in a closed bottle. After 32 days the compounds were crystallized. The procedure was repeated with three different incubating solvents: acetone, ethyl acetate and tetrahydrofuran. In each case, the product obtained was valacyclovir hydrochloride in form EI.
10 Example 25
Valacyclovir hydrochloride was dissolved in a minimum of hot methanol. The methanol solution was incubated in butanol atmosphere for 32 days in a closed bottle. After 32 days the compounds were crystallized, yielding valacyclovir hydrochloride form EL The procedure was repeated with two different incubating solvents: ethanol abs., butanol. The product obtained was valacyclovir hydrochloride in form EI.
Example 26
Valacyclovir hydrochloride dry was incubated in a solvent atmosphere of ethanol for 1 week. Then the wet sample was analyzed and shown to be valacyclovir hydrochloride form HL
20 Example 27
Valacyclovir hydrochloride dry was incubated in a solvent atmosphere of
methanol for 1 week. Then the wet sample was analyzed and shown to be valacyclovir
hydrochloride form ITL >
25 Preparation of crystalline forms of valacyclovit hydrochloride by the precipitation method:
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Example 28:
General procedure: Three grams of valacyclovir hydrochloride were dissolved in 18 mL of first solvent at about 25° C. The solution was stirred and 300 mL of second solvent were added to the solution. A suspension of a white solid precipitate of valacyclovir hydrochloride was formed.
The suspension was stirred 1 hr and filtered to recover wet cake precipitate. A portion of the wet cake precipitate was analysed by x-ray diffraction to determine the polymorphic form. The wet cake was dried in vacuo at 40 C. The water content and polymorphic form of the dried material were determined.
10 Table A gives the results obtained with several second solvents when water was
the first solvent. Table B gives the results obtained with water as the second solvent.
A

Exp. Solvent Water content (%) X-Ray Results
147-01w ACN IV
147-02 d 9.22 I
152-01 w BuOH IV
152-02 d 5.74 I
154-01w Acetone IV
B

Exp. Solvent Water content (KF, %) X-Ray Results
151-01w ACN IV
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151-02 d 153-01w 6.85 I
BuOH IV
153-02 d 8.72 I
Example 29: Reagents:

t-BOC Valacyclovir, F.W. 424.45 4.5 g (10.5 mmol)
Hydrochloric acid, 37 %, F.W. 36.46 4 mL (47.3 mmol)
Water, F.W. 18.02 19 mL
Thirty-seven percent hydrochloric acid (4 mL) was added dropwise, during 10 min to a suspension of t-BOC-valacyclovir (4.5 g) in Water (19 mL) at 20 -25 °C. The reaction mixture was stirred for about 5 h at 20 -25 °C, cooled with ice water, followed by addition of IP A to this mixture to give a white precipitate. The suspension was stirred for about 1 h 10 at T< 10 °C (ice water bath) and kept at 4 °C overnight The precipitate was filtered off, washed with cold IPA (20 mL) and dried to give valacyclovir HC1 in form V(2.6 g, 68 %), 97.7 % pure by HPLC, 4.07 % of D-isomer.
Example 30:
Reagents:

t-BOC Valacyclovir F.W. 424.45 9.0 g (21.0 mmol)
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Hydrochloric acid, 37 %, F.W. 36.46 8 mL (94.6 mmol)
Water, F.W. 18.02 22 mL
A mixture of t-BOC-valacyclovir (9.0 g, 21 mmol) and water (22 mL) was stirred for about 20 min. to obtain a fine suspension. 37 % hydrochloric acid (8 mL) was added dropwise to this suspension at 20 -25 °C, the reaction mixture was stirred for about 3.5 h at 20 -25 °C, cooled with ice water, followed by addition of EPA (500 mL) to give a white precipitate. The suspension was stirred for about 1 h at T<10 °C (ice water bath) and kept at 4 °C overnight. The white precipitate was filtered off, dried under reduced pressure to N give valacyclovir HC1 in form V (7.0 g, 92 %), 97.9 % pure by HPLC, 4.0 % of D-isomer.
Example 31:
10 A 250-mL double-jacketed reactor was charged with BOC-valacyclovir (15.0g)
and acetic acid (45.0 g) and filled with argon. The obtained mixture was stirred at 50 °C to complete dissolution of all solids and cooled to 25 °C. A mixture of 37% hydrochloric acid (13.9g) and water (30.0 g) was added dropwise over one hour and the solution was stirred for 3 hours at 20 —25 °C. The reaction mixture was filtered and the filtrate was
15 added dropwise at 25 °C over a period of one hour to acetone (188 g). The suspension was then stirred for 2 hours at 25 °C and then at 14 hours at -15°C. The precipitate was filtered off, washed on the filter with cold acetone (28 g) to obtain 19.1 g of wet"product which was dried under reduced pressure at 25 °C to a constant weight to give 10.8 g (84.9%) of
) valacyclovir hydrochloride in form VI with 98.67% purity by HPLC. Both the wet and
20 dry products contain valacyclovir hydrochloride in form VI, as characterized by X-ray powder diffraction.
Example 32:
A 50-mL reactor was charged with a crude valacyclovir HCL (8.8 g) and water (35.2 g). The obtained mixture was stirred at 40 °C to complete dissolution of all solids and a solution was filtered. The filtrate was added to acetone (132 g) at 40 °C, a
suspension was stirred for 2 hours at 20 °C and 12 hours at -15 °C. The precipitated solid was filtered off, washed on the filter with cold acetone (20 g) to give valacyclovir
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hydrochloride form VII, as characterized by X-ray powder diffraction. This method produced valacyclovir hydrochloride in form VII with 99% purity by HPLC.
Preparation of valacyclovir form I by the thermal method:
Example 33:
5 Valacyclovir hydrochloride form IV was dried to constant at reduced pressure at
40 - 50°C. Analysis of the sampel showed it to be form I.
Preparation of valacyclovir form I by the evaporative method:
Example 34:
Two grams of valacyclovir hydrochloride were dissolved in 250 mL of methanol at 40° C. The methanol was evaporated at 40° C under reduced pressure to obtain form I.
Preparation of Valacyclovir Monohydrate by a Precipitation Method
Example 35
AIL reactor was charged with crude valacyclovir hydrochloride (180 g) and water (720 g). The mixture was heated to and stirred at about 40°C to effect dissolution of
15 the solids. The solution was filtered and me filtered solution was added to 2-propanol (2700 g) in a 6L double-jacketed reactor at 40°C to form a suspension. The suspension formed was stirred for 2 hours at 25°C and the 4 hours at -15°C. The precipitated sohds were collected by filtration, washed with cold 2-propanol (1440 g) and dried to constant weight under reduced pressure to yield 148.5 g (82.5%) of valacyclovir monohydrate with
20 99.52 area-% purity by HPLC, assay 96.7% by HC104 titration assay, assay 95.0% by AgN03 titration. The water content (Karl-Fisher) of the product was 3.45%. The loss on drying (TGA) was 4.5%.
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WE CLAIM:
1. Valacyclovir hydrochloride form I.
2. Valacyclovir hydrochloride form I, as claimed in claim 1 characterized by x-ray diffraction reflections at about 3.7°, 8.6°, 10.6°, 10.9°, 16.5°, 24.0° and 27.2°+0.2° 20.
3. Valacyclovir hydrochloride form I as claimed in claim 2, further characterized by x-ray differaction reflections at about 9.5°, 10.9°, 20.1°, 21.4° and 26.7°+0.2° 20.
4. Valacyclovir hydrochloride form I as claimed in claim 2, further characterized as having a weight loss of between about 6% and about 9% as measured by thermogravimetric analysis over the temperature range between about 25°C and about 125°C.
5. Valacyclovir hydrochloride form I as claimed in claim 1 characterized by the x-ray diffraction pattern substantially as shown in figure I.
6. Valacyclovir hydrochloride sesquihydrate.
7. Valacyclovir hydrochloride form II.
8. Valacyclovir hydrochloride form II as claimed in claim 7 characterized by x-ray diffraction reflections at about 6.6°, 19.0°, 21.5°, 27.4° and 28.5°+0.2° 20.
9. Valacyclovir hydrochloride form II as claimed in claim 8 further characterized by x-ray diffraction reflections at about 9.2°, 15.6° and 26.3°+0.2° 20.
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10. Valacyclovir hydrochloride form II as claimed in claim 8 further characterized as having an endothermic peak at about 214°C by differential thermal analysis.
11. Valacyclovir hydrochloride form II as claimed in claim 7 characterized by the x-ray diffraction pattern substantially as shown in figure 3.
12. Valacyclovir hydrochloride form IV.
13. Valacyclovir hydrochloride form IV as claimed in claim 12
characterized by the x-ray diffraction pattern substantially as shown in
figure 6.
14. Valacyclovir hydrochloride form IV as claimed in claim 12 characterized by x-ray diffraction reflections at about 3.6°, 10.7°, 15.1°, 26.9oand28.1°+O.2°20.
15. Valacyclovir hydrochloride form IV as claimed in claim 14 further characterized by x-ray diffraction reflections at about 7.2°, 8.6°, 9.5°, 13.3°, 15.2° and 27.3°, and 28.1°+0.2° 20.
16. Valacyclovir hydrochloride form IV as claimed in claim 14 further characterized as having a water content between about 8% and about 11% as measured by thermogravimetric analysis over the temperature range between about 25° and about 130°C.
17. Valacyclovir hydrochloride form V.
18. Valacyclovir hydrochloride form V as claimed in claim 17 characterized by the x-ray diffraction pattern substantially as shown in figure 7.
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19. Valacyclovir hydrochloride form V as claimed in claim 17 characterized by x-ray diffraction reflections at about 6.7°, 15.7°, 16.2° and 22.6°±0.2° 29.
20. Valacyclovir hydrochloride form V as claimed in claim 19 further characterized by additional x-ray diffraction reflections at about 3.4°, 9.5°, 13.5°, 21.9°, 27.2° and 28.6+0.2° 26.
21. Valacyclovir hydrochloride form V as claimed in claim 19 further characterized as having a weight loss of between about 5% and about 7% as measured by thermogravimetric analysis over the temperature range between about 25°C and about 130°C.
22. Valacyclovir hydrochloride form V as claimed in claim 21 further characterized by a board endothermic peak at about 95°C and a sharp endothermic peak at about 180°C in differential thermal analysis.
23. Valacyclovir hydrochloride form VI.
24. Valacyclovir hydrochloride form VI as claimed in claim 23 characterized by the x-ray diffraction pattern substantially as shown in figure 9.
25. Valacyclovir hydrochloride form VI as claimed in claim 23 characterized by x-ray diffraction reflections at about 6.2°, 9.2°, 12.1°, 20.2° and 25.7°+0.2° 20.
26. Valacyclovir hydrochloride form VII.
27. Valacyclovir hydrochloride form VII as claimed in claim 26 characterized by x-ray diffraction reflections about 3.5°, 10.3°, 13.6°, 26.2° and 28.1°+0.2° 20.
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28. Valacyclovir hydrochloride form VII as claimed in claim 26 characterized by the x-ray diffraction pattern substantially as shown in figure 10.
29. A method of making valacyclovir hydrochloride form I comprising the step of slurrying valacyclovir hydrochloride in a slurry solvent selected from the group consisting of ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylene chloride, t-butyl methyl ether, and tetrahydrofurane.
30. The method as claimed in claim 29, further comprising the steps of:
isolating valacyclovir hydrochloride in form I from the slurry and
drying valacyclovir form I at a temperature between about 50 °C and about 70°C.
31. A method of making valacyclovir hydrochloride in form V comprising the step of mixing a solution of valacyclovir in water with hydrochloric acid; admixing a lower aliphatic alcohol; and recovering valacyclovir form V.
32. The method as claimed in claim 31, wherein the lower aliqhatic alcohol is iso-propanol.
33. A method of making valacyclovir hydrochloride in form I comprising the steps of dissolving valacyclovir hydrochloride in a solvent, and evaporating the solution at a reduced pressure.
34. The method as claimed in claim 33, wherein the solvent is a polar organic solvent having 4 or fewer carbon atoms.
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35. The method as claimed in claim 34, wherein the polar organic solvent is an alcohol.
36. The method as claimed in claim 35, wherein the solvent is methanol.
37. A pharmaceutical composition comprising at least one of valacyclovir hydrochloride in forms I, II, IV, V, VI or VII.
38. The pharmaceutical composition as claimed in claim 34 further comprising at least one pharmaceutically acceptable excipeint.
39. Valacyclovir hydrochloride dihydrate.

Dated this 13th day of April, 2006.


[DEEPA KAGHROOTIKU]
Of REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

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