Process for preparing atazanavir bisulfate and novel forms

The preparation method of atazanavir bisulfate and its novel form

Process for preparing atazanavir bisulfate and novel forms

Related application information

In this case, priority was granted to the U.S. provisional applications 60/568043 (filed on May 4, 2004) and 60/607533 (filed on September 7, 2004), the disclosure of which is also the reference material of this article.

The present invention relates to a method for preparing HIV protease inhibitor atazanavir bisulfate and its novel form.

U.S. Patent No. 5,849,911 (F<img file="TWI445697B_D0001.tif" he="30" id="i0001" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="21" />ssler et al.) revealed a series of HIV protein enzyme inhibitors (including atazanavir), which have the following structure:<chemistry general="n"><img file="TWI445697B_D0002.tif" he="362" id="i0002" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="822" /></chemistry>Where: R₁It is a low alkoxycarbonyl group, R₂It is the second or third level lower alkyl group or lower alkylthio-lower alkyl group, R₃Is phenyl substituted with or without one or more lower alkoxy groups, or C₄-C₈Cycloalkyl, R₄Is a phenyl group or a cyclohexyl group, which respectively have 5-8 ring atoms at the 4th position and contain 1 to 4 selected from the group consisting of nitrogen atoms, oxygen atoms, sulfur atoms, sulfinyl (-SO-) andBase (-SO₂-) heteroatom and unsubstituted or substituted by unsaturated heterocyclic group substituted by lower alkyl group or phenyl-lower alkyl group (bonded via ring carbon atom), R₅Department of R₂Irrelevant but with R₂One of the definitions, and R₆Department of R₁Irrelevant is an alkoxycarbonyl group, or a salt thereof, except that the prerequisite is that there is at least one salt-forming group, which includes various pharmaceutically acceptable acid addition salts.

A variety of methods for the preparation of atazanavir have been proposed, including the preparation of one in which R₁And R₆And R₂And R₅Each is a compound of the same group, among which, the diamino compound shown in the following structural formula:<chemistry general="n"><img file="TWI445697B_D0003.tif" he="399" id="i0003" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1173" /></chemistry>

Condensation reaction with the acid shown in the following structural formula or its reactive acid derivative,<chemistry general="n"><img file="TWI445697B_D0004.tif" he="345" id="i0004" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1206" /></chemistry>

Where R₁"And R₂'Department as R₁And R₆And R₂And R₅definition.

In the formation of atazanavir using the above method, a diamino compound (a) having the following structure<chemistry general="n"><img file="TWI445697B_D0005.tif" he="618" id="i0005" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="835" /></chemistry>

Is composed of epoxides:<chemistry general="n"><img file="TWI445697B_D0006.tif" he="400" id="i0006" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="539" /></chemistry>

With (hyrazinocarbamate):<chemistry general="n"><img file="TWI445697B_D0007.tif" he="225" id="i0007" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="809" /></chemistry>

Coupling reaction in the presence of isopropanol to form a protected diamine:<chemistry general="n"><img file="TWI445697B_D0008.tif" he="618" id="i0008" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="809" /></chemistry>

It is treated with hydrochloric acid in the presence of a solvent such as tetrahydrofuran to form a diamine (a)<chemistry general="n"><img file="TWI445697B_D0009.tif" he="598" id="i0009" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="743" /></chemistry>

This diamine is separated and used in the subsequent coupling step to neutralize the acid (b):<chemistry general="n"><img file="TWI445697B_D0010.tif" he="305" id="i0010" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="601" /></chemistry>

Or its reactive ester reaction, which uses such as O-(1,2-dihydro-2-oxo complex-1-pyridyl)-N,N,N¹, N¹-Tetramethyl aldehyde-tetrafluoro-borate (TPTU) coupling agent.

We know that diamine free base is unstable, therefore, it is not suitable for the preparation of atazanavir free base.

U.S. Patent No. 6087383 (Singh et al.) discloses an azapeptide HIV protease inhibitor called atazanavir represented by the following structural formula:<chemistry general="n"><img file="TWI445697B_D0011.tif" he="608" id="i0011" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1189" /></chemistry>

(Also known as atazanavir bisulfate or atazanavir sulfate).

Example 3 of Singh et al. illustrates Type-II crystal form (which is a hydrated and hygroscopic crystal form) and Type-I form crystal (which is an anhydrous/solvated crystalline form) atazanavir hydrogen sulfate Preparation of salt.

Brief description of the invention

The present invention provides atazanavir bisulfate, which includes Pattern C material and Form E3. E3 form (Form E3) is preferred.

In addition, the present invention also provides a novel form of atazanavir bisulfate salt A crystals (a large number of drugs, which are the Type-I crystals in Example 3 of US Patent No. 6,0,87,383 (Singh et al.)) The system of law. Form A crystals prepared by the method of the present invention have the uniform particle size and average particle size actually required and are used for conversion into C-type substances (partially crystalline substances), which are formulated into drugs with various excipients.

The method for preparing the atazanavir bisulfate salt A crystals of the present invention adopts an improved cubic crystallization technology, wherein the sulfuric acid is added at an increased rate according to the cubic equation (described below) and includes A solution of atazanavir free alkali in an organic solvent (wherein, atazanavir bisulfate is essentially insoluble) and less than about 15% by weight (preferably about 12% by weight) tower The first part of the concentrated sulfuric acid reaction with the amount of atazanavir free alkali is added to the reaction mixture with the seed crystals of the form A crystals of atazanavir bisulfate salt, when atazanavir sulfuric acid When hydrogen salt crystals are formed, in multiple steps, according to the cubic equation, additional concentrated sulfuric acid is added while increasing the rate to form form A crystals.

In addition, the present invention also provides a preparation method of the form of atazanavir, which is derived from and includes atazanavir bisulfate and is called a C-type substance. Type C is prepared by suspending Form A crystals in water and then drying them. Alternatively, the type C substance can be formed by subjecting the form A crystals of atazanavir hydrogen sulfate to a relatively high humidity above about 95% RH (water vapor) for at least 24 hours. Type C substances can also be formed by wet granulation of atazanavir bisulfate or a mixture of atazanavir bisulfate and excipients, followed by drying.

In a preferred system, the Form A crystal system is mixed with formulation excipients, such as one or more bulking agents (for example, lactose), one or more disintegrating agents (for example, crospovidone), and then wet Form granulation directly to form a mixture of type C substances and excipients.

In addition, the present invention also provides a novel form of atazanavir, that is, Form E3, which is a highly crystalline form of atazanavir bisulfate triethanol solvate.

The E3 form is prepared by slurrying the free base of Sinavir in ethanol, treating the slurry with concentrated sulfuric acid and inoculating the resulting solution with ethanol to moisten E3 crystals, and then treating with heptane (or other solvents, such as toluene or hexane). The mixture is made by filtering and drying.

The present invention also provides a method for preparing atazanavir bisulfate salt A crystals, which includes preparing the triamine salt represented by the following structural formula:<chemistry general="n"><img file="TWI445697B_D0012.tif" he="576" id="i0012" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="733" /></chemistry>

(Preferably HCl (3 mol) salt) and without separating the triamine salt, the triamine salt and the active ester are preferably represented by the following structural formula:<chemistry general="n"><img file="TWI445697B_D0013.tif" he="439" id="i0013" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="578" /></chemistry>

It reacts in the presence of a base and an organic solvent to form atazanavir free base solution, which is converted into atazanavir bisulfate via the modified cubic crystallization technique as described herein without being separated.

In addition, the present invention also provides a novel atazanavir bisulfate salt composition, which comprises a form A crystal or a form C substance of atazanavir bisulfate and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include fillers, binders, disintegrating agents, lubricants and other traditional excipients. The various forms of Tasinavir bisulfate of the present invention can be characterized by a variety of techniques, and its operation is learned by those who are familiar with this art. Different forms can be characterized and distinguished using single crystal X-ray diffraction (which is based on the unit cell measurement value of a single crystal of each form at a fixed analysis temperature). A detailed description of the unit cell can be found in Stout &amp; Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is also the reference material for this article. Alternatively, the unique spatial arrangement of atoms in the crystal lattice can be characterized according to atomic fraction coordinates. Another method to characterize the crystal structure is to use powder X-ray diffraction analysis, in which the measured diffraction pattern is compared with the control pattern representing pure powder material (all performed at the same analysis temperature), and the measured value of the experimental form is based on a Characterization of the 2θ value of the series. Other methods of characterizing each form can be used, such as solid phase nuclear magnetic resonance (SSNMR), thermal differential scanning analysis (DSC), and thermogravimetric analysis (TGA). These parameters can be combined to characterize various forms.

Form A crystals can be characterized by unit cell parameters that are actually equal to the following:

Cell dimension:

a=9.86(5)Å

b=29.245(6)Å

c=8.327(2)Å

α=93.56(2)°

β=114.77(3)°

γ=80.49(3)°

Space group 1

Molecule/asymmetric unit 2

The crystal form is at about +22°C.

Form A has the characteristics of the atomic fraction coordinates actually listed in Table 3 and the crystal structure actually shown in FIG. 2.

Form A has actually the characteristics of the control and measured powder X-ray diffraction patterns shown in FIG. 1.

Form A has the characteristics of the thermal differential scanning analysis temperature record (DSC) of the endothermic peak starting at about 165.6°C as shown in FIG. 3 in fact.

Form A has the characteristics of a thermogravimetric analysis (TGA) graph with negligible weight loss up to about 100°C-150°C, as shown in FIG. 4 in fact.

Form A has the characteristics of the solid state NMR (SSNMR) chemical shifts actually shown in Table 4 and the spectra shown in FIG. 5 in fact.

Form A has actually the characteristics of the atomic fraction coordinates listed in Table 5.

Form A has a humidity-absorption isotherm characteristic of about 0.1% weight increase in the range of 25°C and 25-75%RH.

In another object of the present invention, type C has the heat of about 4.4% weight loss at about 125°C and about 4.4% weight loss at about 125°C as shown in FIG. 8. Gravimetric analysis curve characteristics.

According to the present invention, the E3 form has the characteristics of the crystallization data shown in Table 5, which is actually equal to the following:

a=10.749(5)Å

b=13.450(4)Å

c=9.250(2)Å

α=98.33(2)°

β=95.92(3)°

γ=102.82(3)°

Space group P1

Molecule/asymmetric unit 1

When the crystal form is at about -23°C.

In the different purposes of the present invention, the E3 form has the characteristics of atomic fraction coordinates as shown in Table 6.

In the different purposes of the present invention, the E3 form has the characteristics of the control and actual powder X-ray diffraction patterns shown in FIG. 9 in fact.

Among the different purposes of the present invention, the E3 form has the characteristic of thermal differential scanning analysis temperature record (DSC), which is actually shown in FIG. 11, which generally absorbs heat in the range of about 89.4°C to about 96.6°C.

In the different purposes of the present invention, the E3 form has the characteristics of a thermogravimetric analysis curve that actually shows a weight loss of about 14.7% at about 150°C as shown in Table 8.

In the different purposes of the present invention, the E3 form has actually the crystal structure characteristics shown in FIG. 10.

Detailed description of the invention

At least part of the present invention provides novel substances of atazanavir bisulfate in different forms (ie, E3 form and C form), especially pharmaceutically acceptable forms. As used herein, the term "pharmaceutically acceptable" refers to within the scope of reasonable pharmaceutical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or a reasonable benefit/risk ratio Compounds, substances and compositions that are commensurate with other complications. In some preferred systems, the crystalline form of the free base I and its salts is actually in its pure form. As used herein, the term "actually pure" refers to a purity greater than about 90%, which includes, for example, about 91%, about 92, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100% compound.

As used herein, the term "polymorph" refers to a crystal form in which the molecules, atoms and/or ions that have the same chemical composition but form the crystal have different spatial arrangements.

As used herein, the term "solvate" refers to a crystalline form of molecules, atoms and/or ions that also contain solvent molecules incorporated into the crystal structure. The solvent molecules in the solvate can be arranged regularly or irregularly. Solvates may contain chemical and/or non-chemical amounts of solvent molecules. For example, a solvate with a non-chemical dose of solvent molecules can result from the partial loss of solvent from the solvate.

The sample of the crystal form can be in fact pure state uniformity, which represents the existence of a major single crystal form and any trace of one or more other crystal forms. The presence of more than one crystal form in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (SSNMR). For example, comparing the measured PXRD pattern with the imitation PXRD pattern, there is an extra peak representing more than one crystal form in the sample. The imitation PXRD pattern can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns, "Lawrence Radiation Laboratory, Livemore, California, UCRL-7196 (April 1963). Ideally, the crystal form has practically pure state uniformity, This is evidenced by the fact that in the measured PXRD pattern, the total peak area is less than 10%, preferably less than 5%, and more preferably less than 2% is due to extra peaks that are not present in the imitated PXRD pattern. Ideally, in the actual measured PXRD pattern, all peak areas less than 1% are derived from the actual pure homogeneous crystal form that imitates the extra peaks that do not exist in the PXRD pattern.

The method of making crystal forms is well-known in this art. The crystal form can be prepared by a variety of methods, including, for example, recrystallization from a suitable solvent, sublimation, growth from a melt, transformation from other states of solid state, crystallization from other supercritical fluids, and jet spraying. Techniques for crystallization or recrystallization of crystal forms from solvent mixtures include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, crystal seeding molecules and/or supercritical solvent mixtures of salts, freeze-drying solvent mixtures, and adding antisolvents To the solvent mixture.

Drug crystals, including polymorphs, preparation methods, and characteristics of drug crystals are discussed in Solid-State Chemistry of Drug, SR Byrn, RR Pfeiffer, and JG Stowell, second edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques using solvents, the choice of solvent is usually determined by one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Solvents can be used in combination. For example, the compound can be dissolved in the first solvent to obtain a solution, and then an antisolvent is added to reduce the solubility of the compound in the solution to form crystals. The antisolvent is a solvent in which the compound has low solubility. Suitable solvents for crystal preparation include polar and non-polar solvents.

In one method of preparing crystals, atazanavir bisulfate is suspended and/or stirred in a suitable solvent to form a slurry, which can be heated to promote its dissolution. As used herein, the term "slurry" refers to a saturated solution of atazanavir bisulfate or its salts, which may also contain additional amounts of atazanavir bisulfate or Its salts are obtained at a given temperature of atazanavir bisulfate or a heterogeneous mixture of its salts and solvents. Suitable solvents in this aspect include, for example, polar aprotic solvents, polar protic solvents, and mixtures of two or more solvents as disclosed herein.

Seed crystals can be added to any crystallization mixture to promote crystallization. As people familiar with this art have seen, inoculation is used as a method to control the growth of a specific crystal form or as a method to control the particle size distribution of the crystal product. Therefore, the calculation of the required number of seed crystals is determined by the size of the available seed crystals and the appropriate size of the average product particles, such as "Programmed cooling of batch crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science (1971) 26 : Discussed in 369-377. Generally speaking, small-sized seed crystals are needed to effectively control the growth of crystals in the batch. Small-sized seed crystals can be obtained by screening, grinding, or micronizing large crystals. Care must be taken to avoid changing the crystal form to an unwanted crystal form (ie, becoming amorphous or other polymorphs) when the crystals are milled or micronized.

The cooled mixture is filtered under vacuum, the separated solid is washed with a suitable solvent (such as a cold recrystallization solvent), and then dried under a nitrogen stream to obtain the desired crystal form. The separated crystals are analyzed using appropriate spectroscopy or analytical techniques (such as SSNMR, DSC, PXRD, etc.) to determine the more ideal crystal form of the formed product. The yield of the obtained crystalline form is usually greater than about 70% by weight, but preferably greater than 90% by weight separation yield (based on the weight of atazanavir bisulfate originally used in the crystallization process). If necessary, grind the product together and pass it through a screen to remove the agglomerated product.

The crystalline form can be directly prepared from the reaction medium in the final step of preparing atazanavir bisulfate. This can be achieved by using a solvent or solvent mixture from which atazanavir bisulfate can crystallize in the final step. Another feasible method is to use distillation or solvent addition techniques to obtain crystal forms. Solvents suitable for this purpose include any of the solvents mentioned herein, including polar protic solvents (such as ethanol) and polar aprotic solvents (such as acetone).

Following general guidelines, the reaction mixture can be filtered to remove any unwanted impurities, inorganic salts, etc., followed by washing with a reaction or crystallization solvent. The resulting solution can be concentrated to remove excess solvent or gaseous components. If the distillation method is used, the final amount of distillate collected may vary depending on the requirements of the preparation method (including, for example, the size of the container, the stirring capacity, etc.). According to general guidelines, the reaction mixture can be distilled to one-tenth of its original volume before solvent substitution. According to standard preparation techniques, samples can be taken and the reaction can be analyzed to determine the degree of reaction and the weight% of the product. If necessary, additional reaction solvent can be added or removed to optimize the reaction concentration. Preferably, the final concentration is adjusted to about 50% by weight, in which case a slurry is usually formed.

It is more convenient to directly add the solvent to the reaction vessel without distilling the reaction mixture. The suitable solvent for this purpose is the solvent that finally participates in the crystal lattice as discussed in the solvent exchange above. Although the final concentration may vary depending on the desired purity, recovery, and other factors, the final concentration of free alkali (I) in the solution is preferably about 4% to about 7%. The reaction mixture can be stirred and warmed at the same time after adding the solvent. For example, the reaction mixture can be stirred for about 1 hour while warming to about 70°C. The reaction is preferably filtered while hot and washed with a reaction solvent, adding a solvent or a mixture thereof. Seed crystals can be added to any crystallization solution to start crystallization.

The various forms mentioned in this article can be distinguished by various analysis techniques commonly used by people who are familiar with this art. These techniques include, but are not limited to, solid state nuclear magnetic resonance spectroscopy (SSNMR) spectroscopy, powder X-ray diffraction (PXRD), thermal differential scanning analysis temperature record (DSC), and/or thermogravimetric analysis pattern (TGA).

Generally, those who are familiar with this art will understand that there will be an experimental error in the X-ray diffraction pattern, which depends on the measurement conditions used. It is generally known that the intensity in the X-ray diffraction pattern fluctuates depending on the measurement conditions used and the shape or morphology of the crystal. We also need to understand that the relative intensity also varies with the experimental conditions, so the actual magnitude of the intensity does not need to be taken into consideration. In addition, in traditional X-ray diffraction patterns, the measurement error of the diffraction angle is usually about 0.2% or less, preferably about 0.1% (as discussed in this article), and this degree of experimental error must be regarded as belonging to the aforementioned diffraction Due to the angle, therefore, it should be understood that the crystal form of the present invention is not limited to the crystal form having the X-ray diffraction pattern completely equal to the X-ray diffraction pattern in the drawings disclosed herein. Any crystal form having an X-ray diffraction pattern substantially equal to that shown in the drawings is within the scope of the present invention. The ability to determine the substantial identity of X-ray diffraction patterns is within the range of those skilled in the art.

As used herein, the term "form" in relation to Form A and Form E3 refers to a uniform crystal structure.

As used herein, the term "type" in the C-type refers to a unique X-ray diffraction pattern.

As used herein, the term "atazanavir bisulfate" refers to atazanavir bisulfate and atazanavir sulfate.

The method for preparing the atazanavir bisulfate salt form A crystals of the present invention adopts an improved cubic technology, which is to dissolve atazanavir free base in an organic solvent (wherein, atazanavir) Atazanavir bisulfate is essentially insoluble and includes acetone, a mixture of acetone and N-methylpyrrolidone, ethanol, a mixture of ethanol and acetone, etc.) and the free alkali concentration of atazanavir is at A solution in the range of about 6.5 to about 9.7% by weight, preferably about 6.9 to about 8.1% by weight.

Atazanavir free alkali solution is heated at a temperature of about 35°C to about 55°C, preferably at a temperature in the range of about 40°C to about 50°C. 15% by weight, preferably about 5 to less than about 12% by weight, and more preferably about 8 to about 10% by weight of atazanavir free alkali. Therefore, the starting solution of atazanavir free base will first be reacted in an amount less than about 15% by weight of the total sulfuric acid used, preferably about 5 to about 12% by weight. During the reaction, the reaction mixture is maintained at a temperature ranging from about 35°C to about 55°C, preferably from about 40°C to about 50°C.

The reaction can last from about 12 minutes to about 60 minutes, preferably from about 40 minutes to about 50 minutes.

The reaction mixture is inoculated with atazanavir bisulfate form A crystals while maintaining the temperature at about 35°C to about 55°C, preferably in the temperature range of about 40°C to about 50°C. The number of seeds used is It is in the range of about 0.1% by weight to about 80% by weight, preferably about 3% by weight to about 8% by weight (based on the weight of atazanavir free base present in the reaction mixture).

Continue the reaction until it starts to crystallize. Thereafter, sulfuric acid was added to form atazanavir bisulfate salt according to the cubic equation described below at an increased rate, which produces form A crystals on drying.

The size and morphology of the formed atazanavir bisulfate crystals are determined by the rate of addition of sulfuric acid, which determines the rate of crystallization. We have found that the improved cubic crystallization technology (acid is added at an increased rate according to the cubic equation) can provide a larger and more clearly defined atazanavir hydrogen sulfate than a fixed addition rate crystallization Salt crystals have a narrower and finer particle size range. The slow initial acid flow rate has been proven to promote crystal growth better than secondary nucleation. Therefore, since the surface area becomes larger as the particle size increases, the seed bed can accept an increase in the acid flow rate without causing second-degree nucleation. The slow initial acid flow rate allows time for the crystals to grow larger, increasing the average size. Cubic crystallization provides a less compressible filter cake, which facilitates effective filter cake deliquoring and washing, and produces a product that contains less lumps and is easier to dry than a fixed addition rate crystallization product.

The cubic crystallization method used is a time-controlled crystallization method derived from Mullin, Crystallixation, Third Edition, 1993, Butterworth-Heineman, Pubs. and it is defined by the following simplified equation:<maths><img file="TWI445697B_D0014.tif" he="229" id="i0020" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1176" /></maths>Where: T_m_a_x=crystallization start time T_m_i_n= Crystallization end time time = crystallization elapsed time time_t_o_t_a_l= Total crystallization time

Because the crystallization of atazanavir bisulfate is controlled by the addition rate of sulfuric acid, in equation (I), the temperature variable is replaced by acid. In this equation, the variable representing the minimum volume is removed.<chemistry general="n"><img file="TWI445697B_D0015.tif" he="269" id="i0021" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1183" /></chemistry>Where: V_t_i_m_e= The volume of sulfuric acid added in a period of time V_t_o_t_a_l= Represents the total volume of 90% acid fed into time = the elapsed time of crystallization time_t_o_t_a_l= Total crystallization time or total time of acid feed.

Equation (2) is called "cubic equation".

Using this description, by controlling the crystallization rate, the nucleation is controlled within an acceptable limit while the system is maintained at a fixed low degree of oversaturation.

Form A crystal system is confirmed by powder X-ray diffraction pattern and crystal structure shown in Figures 1 and 2 respectively.

The A-form crystals or C-form substance of atazanavir bisulfate and the E3 form prepared as shown above are the final atazanavir bisulfate and can be used as pharmaceutical products for patients.

According to the method of the present invention, the Type C substance can be prepared by exposing the Form A crystals in water, followed by drying.

According to another method of the present invention, the type C substance can be exposed to form A crystals in greater than about 95% RH, preferably about 95% RH to about 100% RH (water vapor) for at least 24 hours, preferably about 24 to about 48 Manufactured in hours.

In another system of the present invention, the type C substance is prepared by wet granulation of form A crystals of atazanavir bisulfate to produce atazanavir bisulfate particles, followed by drying The particles are derived.

In the implementation of the wet granulation method, atazanavir bisulfate will be granulated in water and dried at a temperature of about 40°C to about 80°C, preferably about 50°C to about 60°C. The drying step is preferably carried out for at least about 2 hours to as long as about 20 hours, and preferably for about 8 to about 10 hours.

Type C substances can also be prepared by wet granulation in the presence of traditional pharmaceutical excipients (for example, one or more leavening agents (preferably lactose), one or more disintegrating agents (preferably crospovidone)) The form A crystals of atazanavir bisulfate salt are then dried as described above to form a form C substance mixed with excipients.

Atazanavir bisulfate used to prepare drugs for the treatment of diseases caused by viruses as described below is a C-type substance, A or E3 form, preferably a C-type substance.

The E3 form is formed by slurrying the free base of Sina Wei in ethanol, and treating the slurry with concentrated sulfuric acid (the molar concentration ratio of acid: free base is in the range of about 1:1 to about 1.1:1). The resulting mixture is heated at 30°C to about 40°C, the resulting solution is inoculated with ethanol moistened E3 crystals, the mixture is treated with heptane (or other solvents such as hexane or toluene), filtered and dried to prepare Tasnavir ( E3 form of atazanavir bisulfate (triethanol solvate.

The seeding step will use a number of seed crystals that can form E3 crystals, for example, the molar concentration ratio of atazanavir bisulfate E3 seed crystal: free alkali is in the range of about 0.02:1 to about 0.04:1 Inside.

The E3 form is confirmed by the powder X-ray diffraction pattern shown in FIG. 7 and the crystal structure shown in FIG. 6.

According to the present invention, the free base form of atazanavir is prepared by the presence of an organic solvent (such as dichloromethane, tetrahydrofuran, or methanol, which is preferably dichloromethane) at about 25°C to about 50°C , Preferably within the temperature range of about 30°C to about 40°C, treat the protected triamine shown in the following structural formula with acid (preferably hydrochloric acid, where Boc is used), or base (where trifluoroacetyl group is used) Salt:<chemistry general="n"><img file="TWI445697B_D0016.tif" he="567" id="i0022" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="819" /></chemistry>

(In the formula, PG represents a protecting group, such as tertiary butoxycarbonyl (Boc) or trifluoroacetyl group, preferably Boc) to form a triamine salt, which is preferably a hydrochloride salt shown in the following structural formula:<chemistry general="n"><img file="TWI445697B_D0017.tif" he="574" id="i0023" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="749" /></chemistry>

And without separating the triamine salt, make the triamine salt and the active ester of the acid shown in the following structural formula:<chemistry general="n"><img file="TWI445697B_D0018.tif" he="319" id="i0024" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="467" /></chemistry>

It is preferably an active ester represented by the following formula:<chemistry general="n"><img file="TWI445697B_D0019.tif" he="445" id="i0025" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="679" /></chemistry>

In alkali (such as K₂HPO₄, Diisopropylethylamine, N-methylmorpholine, sodium carbonate, or potassium carbonate, preferably K₂HPO₄) And organic solvents (such as dichloromethane, a mixture of ethyl acetate and butyl acetate, CH₃In the presence of CN or ethyl acetate, preferably dichloromethane), it reacts at a temperature of about 25-50°C, preferably about 30-40°C, to form atazanavir free base. The protected triamine starting material is an epoxide represented by the following formula:<chemistry general="n"><img file="TWI445697B_D0020.tif" he="372" id="i0026" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="411" /></chemistry>

In the formula, PG is preferably Boc, such as N- (third butoxycarbonyl)-2-(S)-amino-1-phenyl-3(R)-3,4-epoxybutane, and The hydrazine carbamate represented by the following formula<chemistry general="n"><img file="TWI445697B_D0021.tif" he="229" id="i0027" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="613" /></chemistry>

In the formula, PG is preferably prepared by the reaction of Boc in the presence of isopropanol or other alcohols (such as ethanol or butanol).

Atazanavir bisulfate can be administered to warm-blooded animals (especially humans) for treatment or prevention related to the inhibition of retroviral proteases (such as HIV-I or HIV-II gag protease) Disease (for example, retroviral disease, such as AIDS or its initial stage).

Atazanavir bisulfate, especially C-pattern substance, A-form or E3 form, preferably C-pattern substance or A-form can be used to treat viruses (especially retroviruses) ) In the method for causing disease (especially AIDS or its initial stage), wherein the therapeutically effective amount of atazanavir bisulfate C-type substance that can effectively treat the aforementioned diseases, the A form or the E3 form is administered to Warm-blooded animals suffering from the disease (especially AIDS or its initial stage) and requiring this treatment, such as humans. The preferred dose for administration to warm-blooded animals (for example, humans weighing about 70kg) is about 3 mg to about 1.5 g per person per day, preferably about 50 mg to about 600 mg, and is preferably divided into 1-4 single doses, for example, It can be the same number. Usually, children take one and a half doses of adults. It is suitable for oral administration.

The C Pattern substance of atazanavir bisulfate salt, A form or E3 form is for the above-mentioned pharmaceutical use. Appropriate compositions for oral administration containing C Pattern substances or Form A or Form E3 include tablets, powders, capsules, and tinctures. As required by the acceptable drug use method, about 10-600 mg of active ingredient and pharmaceutically acceptable excipients, carriers, adjuvants, binding agents, preservatives, stabilizers, fragrances, etc. are blended together in a single dosage form.

The pharmaceutical composition for oral administration can be composed of a mixture of active ingredients and a solid carrier, if desired, granulated to obtain a mixture, and if desired or necessary, after adding appropriate excipients, the mixture is processed into tablets, lozenges Core, capsule or powder for oral administration.

The leavening agent or filler will be present in the pharmaceutical composition in an amount of about 0-95% by weight of the composition, preferably about 10-85% by weight. Examples of leavening agents or fillers suitable for use in the present invention are, but not limited to, cellulose derivatives (such as microcrystalline cellulose or lignocellulose), lactose, sucrose, starch, pregelatinized starch, glucose, and glycol , Fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts (such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate), dextrin, maltodextrin, compressible sugars , And other leavening agents or fillers, and/or a mixture of two or more thereof, preferably lactose.

The binding agent will be present in the pharmaceutical composition in an amount of about 0-20% by weight of the composition, preferably about 1-10% by weight. Examples of leavening agents or fillers suitable for use in the present invention are, but not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP) (molecular weight is about 5000-8000 Within the range, it is preferably about 4000), hydroxypropyl methylcellulose (HPMC), lactose, acacia, ethyl cellulose, cellulose acetate, and wax binders (such as carnauba wax, paraffin wax, whale Wax, polyethylene or microcrystalline wax), and other traditional binders, and/or a mixture of two or more thereof, preferably hydroxypropyl cellulose.

The disintegrating powder will be present in the pharmaceutical composition in an amount of about 0-20% by weight of the composition, preferably about 0.25-15% by weight. Examples of leavening agents or fillers suitable for use in the present invention are, but are not limited to, croscarmellose sodium, crospovidone, potato starch, pregelatinized starch, corn starch, sodium starch gluconate, microcrystalline cellulose or Other known disintegrating powders are preferably croscarmellose sodium.

The lubricant will be present in the pharmaceutical composition in an amount of about 0.1-4% by weight of the composition, preferably about 0.2-2% by weight. Examples of lubricants suitable for use in the present invention are, but not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate Or hydrogenated vegetable oils and lipids, or other conventional lubricants for tablet making, and/or a mixture of two or more thereof, preferably magnesium stearate.

The capsule is a hard capsule or a soft sealed capsule made of gelatin and a plasticizer (such as glycerol or sorbitol). Hard capsules contain granular active ingredients and, for example, fillers (such as lactose), combined with both (such as starch, crospovidone) and/or slip agents (such as talc or magnesium stearate), And if needed, stabilizers. In soft capsules, the active ingredients should be dissolved or suspended in appropriate oily excipients (such as fatty oils, paraffin wax or liquid polyethylene glycols. Stabilizers or antibacterial agents may also be added.

The following examples show a more ideal system of the present invention.

Example 1

1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucinyl]amino group}- 4(S)-Hydroxy-6-Phenyl-2-azahexane, Bisulfate (Form A) (Atazanavir Bisulfate-Form A)<chemistry general="n"><img file="TWI445697B_D0022.tif" he="703" id="i0028" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="816" /></chemistry>

(1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis(tert-butoxycarbonyl)amino)]-4(S)-hydroxy-6-benzene 2-Azahexane.3HCl (triamine.3HCl salt)) was added to the protected triamine (1-[ 4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis(tert-butoxycarbonyl)amino)]-4(S)-hydroxy-6-phenyl-2- Azahexane (100g, 0.178mol)<chemistry general="n"><img file="TWI445697B_D0023.tif" he="633" id="i0029" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="798" /></chemistry>

And dichloromethane (500ml; ml/g input protected triamine) (such as Z. Xu et al., Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232,632, Organic Process Research and Development , 6,323-328 (2002)), the resulting slurry was stirred while maintaining a temperature of about 5-22°C. Concentrated sulfuric acid (68ml, 0.82mole, 4.6eq) was added at a rate to maintain the temperature of the reaction mixture at 5-30°C. The reaction mixture was heated and stirring was continued until the reaction was determined to be complete by HPLC analysis.

After adding water (70-210ml, 0.7-2.1ml/g of the input protected triamine) to the reaction mixture and stirring for 15 minutes, the layers were separated. Transfer the upper product (triamine.3HCl salt) to the addition funnel.

<chemistry general="n"><img file="TWI445697B_D0024.tif" he="509" id="i0030" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="605" /></chemistry>(The active ester of N-methoxycarbonyl-L-tert-leucine,<img file="TWI445697B_D0025.tif" he="235" id="i0031" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="364" />)) Add N-methoxycarbonyl-L-tert-leucine (77.2g, 0.408mol , 2.30eq.), 1-hydroxy benzotriazole (HOBT) (60.8g, 0.450mol, 2.53eq.), and N-ethyl-N,-dimethylaminopropyl carbodiimide (carbodiimide ) (EDAC) (82.0g, 0.430mol, 2.42eq.), then add dichloromethane (880ml, 8.8ml/g input protected triamine), stir the mixture at ambient temperature (18-25 °C) until complete Until the formation of active ester (determined by HPLC).

C. 1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(Methoxycarbonyl)-L-tert-leucinyl]amino group }-4(S)-hydroxy-6-phenyl-2-azahexane (atazanavir free base) will be anhydrous potassium phosphate secondary salt (K₂HPO₄; 226g, 1.30mol, 7.30eq. wrt protected triamine) dissolved in 1130 ml water (11.3ml/g protected amine; 5ml/g K₂HPO₄ ）。

This K₂HPO₄The solution is added to the active ester solution prepared in Part B. While continuously stirring and maintaining the reaction temperature at 5-20°C, within 1.5-2.0 hours, stir the active ester/K here₂HPO₄Slowly add part A hydrochloride aqueous solution to the solution.

After the hydrochloride aqueous solution of Part A has been added, the reaction mixture (coupling reaction) is heated to 30-40°C and stirred until the coupling reaction is determined to be complete by HPLC analysis. Cool the coupling mixture to 15-20°C and separate the organic lower layer rich in product from the upper wastewater layer.

1M NaH for product-rich organic layer₂PO₄(880ml; pH=1.5; 8.8ml/g input protected triamine; 5mol eq.wrt protected triamine) wash, separate the layers and remove the upper wastewater layer.

The product-rich organic layer was stirred with 0.5N NaOH (800ml; 8 ml/g of the input protected triamine) until the active ester contained in the product-rich organic layer was less than 0.3II by HPLC analysis. Separate the layers and remove the upper wastewater layer.

Use 5% NaH for product-rich organic layer₂PO₄(450ml; 4.5ml/g of input protected triamine; Ph=4.3) Wash, separate the layers and remove the upper wastewater layer.

The product-rich organic layer was washed with 10 w/v% NaCl (475 ml, 4.75 ml/g protected triamine) and the upper wastewater layer was removed.

The concentration of the free alkali shown in the title is 120-150mg/ml, and the yield calculated for this process is 95-100 mol%.

D. From dichloromethane solvent exchange to acetone/N-methylpyrrolidone in a 3000 ml three-necked round-bottomed flask equipped with a mechanical stirrer, a temperature detector and a distillation condenser in a free alkali solution rich in part C Add N-methylpyrrolidone (148ml; 1.25ml/g free base, based on the quantitative analysis in the process). Concentrate the solution to about 360ml (2.5-3.5ml/g part C free base) using a sleeve temperature of 70°C or below; add 500 ml acetone (4-5 ml/g part C free base) to the concentrated solution and The volume of the distillation mixture is about 400ml or less.

The addition of acetone and distillation were repeated until the end point of the methylene chloride value reached the standard is shown by the process analysis. Under the crystallization volume, the dichloromethane content in the product-rich organic layer is 0.77 v/v%. Acetone is added to the free base concentrated solution to reach a total solution of 16 ml/g free base. Maintain the tank temperature at 40-50°C to avoid crystallization of free alkali. While maintaining the temperature at 40-50°C, the solution is filtered and polished through a 10-micron or below filter. The polished filter was washed with acetone (1.25 ml, 1.0 ml/g free base), and then the lotion was added to the free base-rich acetone/N-methylpyrrolidone solution for use in the next step.

E. 1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(Methoxycarbonyl)-L-tert-leucinyl]amino group }-4(S)-Hydroxy-6-Phenyl-2-azahexane Bisulfate while maintaining the temperature at 40-50°C, it will account for about 10% of the total feed from below the surface (2g) Concentrated sulfuric acid (19g, 1.10eq) was added to the acetone/N-methylpyrrolidone solution of part D free alkali.

The reaction mixture is inoculated with 5.0 wt% (wrt is calculated based on the free alkali in the solution) bisulfate. The inoculated mixture is stirred at 40-50°C for at least 30 minutes. During this time, the bisulfate salt begins to crystallize, which is evidenced by the increase in the opacity of the mixture during this time.

While maintaining the temperature at 40-50°C, the remaining sulfuric acid (17.8g) was added in five steps according to the following experimental draft defined by the cubic equation within about 5 hours.

The rate of each addition step was determined according to the cubic equation as described above and is shown in the table below.

<tables><img file="twi445697b_d0026.tif" he="580" id="i0032" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1623" /></tables>

After the sulfuric acid is added, cool the slurry to 20-25°C while stirring for at least one hour. Stir the slurry at 20-25°C for at least one hour. Filter the bisulfate and recover the mother liquor if necessary to promote its complete conversion. The filter cake is washed with acetone (5-10 ml/g free base; 1200 ml acetone). The bisulfate salt was dried under vacuum at NMT55°C until LOD&lt;1% to produce crystalline material.

The crystalline product was analyzed by PXRD, DSC and TGA patterns and SSNMR spectroscopy, and it was found that it was the titled (unsolvated) bisulfate form A crystal (see Figures 1-5).

<tables><img file="twi445697b_d0027.tif" he="411" id="i0033" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1881" /></tables>T = the temperature of the crystallization data (°C) Z'= the number of drug molecules per asymmetric unit

<tables><img file="twi445697b_d0028.tif" he="1386" id="i0034" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1690" /></tables><tables><img file="twi445697b_d0029.tif" he="2845" id="i0035" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1717" /></tables><tables><img file="twi445697b_d0030.tif" he="2855" id="i0036" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1685" /></tables><tables><img file="twi445697b_d0031.tif" he="904" id="i0037" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1626" /></tables>

Most of the hydrogen atoms are omitted; only hydrogen atoms on N9 and acids are included.

The refined isotropic atom system is defined as: (4/3)*[a2*B(1,1)+b2*B(2,2)+c2*B(3,3)+ab(cos gamma)*B(1 ,2)x+ac(cos beta)*B(1,3)+bc(cos alpha)*B(2,3)] is represented in the form of isotropic and identical replacement parameters.<img file="TWI445697B_D0032.tif" he="16" id="i0038" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="1842" />

Form A is characterized by the differential scanning calorimery thermogram, which generally absorbs heat in the range of about 165.6° C. to about 200.9° C., as shown in FIG. 3.

Form A is also characterized by a thermogravimetric curve with negligible weight loss up to about 100°C to about 150°C.

Compared with crystals prepared by crystallization at a fixed addition rate, the crystals prepared from cubic crystals (where sulfuric acid is added at an increased rate according to the above cubic equation) have larger particles and more clearly defined particles, and have narrower particles. The particle size distribution range and smaller fineness.

The filter cake made by the cubic crystallization technology is less compressible than the filter cake made by crystallization at a fixed addition rate, which helps the filter cake to be effectively deliquored and washed and produce a uniform product.<tables><img file="twi445697b_d0033.tif" he="2295" id="i0039" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1884" /></tables>

Example 2

Atazanavir bisulfate-type C substance Method A: Atazanavir bisulfate form A crystals (prepared as described in Example 1) (25.33g) suspended in 200 ml water And the mixture is mechanically stirred to produce a viscous gel (which is dried).

The dried mixture was ground with a spoon to produce type C material. The powder X-ray diffraction pattern of the C-type substance is shown in Fig. 6.

Method B: Atazanavir bisulfate form A crystals are wet-granulated in a suitable mixer-granulator with sufficient water (approximately 40% w/w). The wet block is dried in an oven. Screen the product with an appropriate screen. The powder X-ray diffraction pattern of the obtained product is shown in Fig. 6, which is consistent with the C-type substance. .

Type C is characterized by differential scanning calorimery thermograms, which generally end up in the range of about 76.7°C to about 96.6°C and about 156.8°C to about 165.9°C, as shown in FIG.

Type C is also characterized by a thermogravimetric analysis curve with a weight loss of 2.4% at about 125°C and a weight loss of 4.4% at about 190°C, as shown in FIG. 7.

Example 3

Atazanavir bisulfate-E3 form (triethanol solvate) is placed in an isobaric liquid addition funnel equipped with a mechanical stirrer and a temperature sensor to make atazanavir free alkali (as in Example 1 , Prepared as described in Part C) (3.0g, 4.26mmol) slurried in dry 200 proof ethanol (20.25ml, 6.75ml/g free base).

Concentrated sulfuric acid (0.25ml, 0.46mmol, 1.1eq.) was added to the atazanavir free alkali slurry maintained at 20-25°C. The resulting solution (KFof 0.2-1.0% water) was polished and filtered (Whatman# 1 filter paper), the filtrate was washed with 2.25 ml of absolute ethanol and the lotion was added to the filtered solution. The solution was heated to 37° C. and 10 mg of amorphous atazanavir bisulfate derived from E3 form crystals (obtained by exposing E3 form crystals to ambient temperature) was used. Then, the mixture was stirred for 15 minutes. Add heptane (380ml, 8.25ml/g free base) within one hour. The resulting crystalline mixture was stirred at 15-25°C for 8 hours. At B<img file="TWI445697B_D0034.tif" he="31" id="i0040" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="24" />Filter the crystallized atazanavir bisulfate on the chner funnel. The product filter cake was washed with 184ml (4ml/g free base) 1:1 ethanol:heptane. The product filter cake was washed with 46 ml (1 ml/g free base) heptane. The resulting product was dried under vacuum at 40-50°C until its LOD=0.97%. The yield of the product was 47.7 g (0.0594 mol, 74.3 mol%) of atazanavir bisulfate E3 crystal form (triethanol solvate), HPLC HI = 100.0 (see Figures 9 and 10).

<tables><img file="twi445697b_d0035.tif" he="422" id="i0041" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1838" /></tables>T = the temperature of the crystallization data (°C) Z = the number of drug molecules per asymmetric unit

<tables><img file="twi445697b_d0036.tif" he="917" id="i0042" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1772" /></tables>

Most of the hydrogen atoms are omitted; only hydrogen atoms on N9 and acids are included.

The refined isotropic atom system is defined as: (4/3)*[a2*B(1,1)+b2*B(2,2)+c2*B(3,3)+ab(cos gamma)*B(1 ,2)x+ac(cosbeta)*B(1,3)+bc(cosalpha)*B(2,3)] is represented in the form of isotropic and identical replacement parameters.<img file="TWI445697B_D0037.tif" he="17" id="i0043" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="1843" />

The E3 format is characterized by the differential scanning calorimery thermogram, which generally absorbs heat in the range of about 89.4° C. to about 96.6° C., as shown in FIG. 11.

Type C is also characterized by a thermogravimetric analysis curve with a weight loss of 14.7% at about 150°C as shown in FIG. 11.

Example 4

The C-type atazanavir bisulfate capsule blend with the following components was prepared as described below.

<tables><img file="twi445697b_d0038.tif" he="1653" id="i0044" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1954" /></tables>

a Use the original granules (55.5% w/w free base) of atazanavir bisulfate capsules to make 50mg, 100mg. And the quantity of 200mg capsule b is expressed on the premise that atazanavir bisulfate is 100% potency, and is equal to 55.5% w/w as the free base.

c The total amount of milk, hydration will vary depending on the purity of atazanavir bisulfate and the amount of magnesium stearate used. d The amount of magnesium stearate used can range from 0.4% w/w to 0.8% w/we. The original particles of atazanavir bisulfate for processing and removal by drying are prepared as follows, wherein a C-type substance is formed.

Atazanavir bisulfate salt form A crystals, lactose hydrate and a part of crospovidone (3% by weight in all crospovidone present) are mixed in a factory-grade mixer. The resulting blend was wet-granulated with pure water to convert the A form to the C form. The wet particles are dried in a disc dryer and sieved by a hammer mill. The remaining crospovidone is added to the milled granules and mixed in the PK V-blender. Magnesium stearate is added and mixed with it until a substantially uniform raw granule is formed.

Fill the capsules with proper weight of the original granules to produce 50mg, 100mg and 200mg capsules containing atazanavir bisulfate.

Example 5

The oral formulation of atazanavir bisulfate salt form A powder with the following composition was prepared as described below.

<tables><img file="twi445697b_d0039.tif" he="862" id="i0045" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" wi="1861" /></tables>

Form A, atazanavir bisulfate, aspartame, phenylalanine methyl ester, orange vanilla flavor and sucrose are mixed together in a suitable mixer. The mixture is ground with a hammer mill, followed by two-degree mixing to obtain a homogeneous mixture. Fill the product into a high-density polyethylene bottle.

Figure 1 shows the powder X-ray diffraction pattern of Form A (CuKαλ=1.5418<img file="TWI445697B_D0040.tif" he="42" id="i0046" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="34" />) Calculated (imitation) (22°C) and measured (experimental at room temperature) values; Figure 2 shows the crystal structure of Form A; Figure 3 shows the thermal differential scanning analysis temperature record (DSC) of Form A; Figure 4 shows the thermogravimetric analysis pattern (TGA) of form A; Figure 5 shows the C-13 solid phase NMR of form A; Figure 6 shows the powder X-ray diffraction pattern of form C (CuKαλ=1.5418<img file="TWI445697B_D0041.tif" he="43" id="i0047" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="34" />) Measured (experimented at room temperature) value; Fig. 7 shows the thermal differential scanning analysis temperature record of C type; Fig. 8 shows the thermogravimetric analysis graph of C type; Fig. 9 shows the powder X of E3 formula Ray diffraction pattern (CuKαλ=1.5418<img file="TWI445697B_D0042.tif" he="42" id="i0048" img-content="character" img-format="tif" inline="no" orientation="portrait" wi="32" />) Calculated (imitated) (22°C) and measured (experimented at room temperature) values; Figure 10 shows the crystal structure of E3 form; and Figure 11 shows the thermal differential scanning analysis temperature record (DSC) of E3 form , And E3 form of thermogravimetric analysis graph.