SA06270303B1 - new crystalline modification lopinavir - Google Patents

Abstract

Abstract: The present invention describes novel crystalline forms of lopinavir.

Description

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A new modified crystalline form of lopinavir

New crystalline modification Lopinavir Full description Background and date 107757976 This application is a partial application of the original application filed under No. H1;77/8/1°-1-(58 “SY ¢SY) New from crystalline forms This invention relates to crystalline forms

VY) om Saad (Methylphenoxyacetylene)‎ EET CY

EO = ad (1)tetrahydropyrimidonyl-7-methylbutanyl) (25,35,58)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(I-hexane) Jd (also known as tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane 01 and methods for its preparation. The new crystalline forms according to the invention (lopinavir) can be used to reliably or separate lopinavir. 10108: Or to prepare lopinavir pharmaceutical compositions to administer lopinavir pharmaceutical compositions 2 General description of the choice Human immunodeficiency virus (HIV) inhibitors Human immunodeficiency virus (HIV) inhibitors have been approved for years in the treatment of human immunodeficiency virus (HIV) infection. One of the protease inhibitors is methylphenoxyacetyl(-amino-?"-hydroxy-0-GET 57; 55)-7-(7;) SY) the compound THO aad hydropyrimidonil (1))-7-methylbutatoyl) trans-1-7((25,38,55)-2-(2,6-dimethylphenoxyacetyl)-amino-3- dy-hydroxy-5-phylhexane (also known as (2-(I-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane . (lopinavir b lopinavir

YYo)

. cto OH 0 9 NY A YY CH, 0 2 0 ri TU HC” lopinavir Lopinavir is known to be used to inhibit protease 1117 and inhibit HIV infection, and lopinavir is particularly effective for inhibiting Clopinavir, when combined with critonavir, is also particularly effective in inhibiting B1117 infection when it is used in combination with one or more enzyme inhibitors. reverse transcriptase and/or one or more other protease inhibitor 1117. Lopinavir and the processes for its preparation are described in US Patent No. © 2414777; Issued on YY Jun 999 a) and cited in this release by reference. This patent also describes processes for preparing amorphous lopinavir and pharmaceutical compositions containing lopinavir or an acceptable salt of it, Gana, are described in US Patent No. 2,914,777; Issued YY JUNE £21499 alla US Patent No. 8/917495; Filed November 17, 1997; Patent Application 1 - Provisional US Patent No. 1977070/10; filed Jan 19; 1007 CE and the US patent application serial number 487774/59; pagal on January 19, 1007 AD, and they are all mentioned in this statement for reference. It has been discovered unexpectedly at present that lopinavir 7 can be prepared and separated in a number of crystal forms.

Brief explanation of the drawings Figure 1: shows the X-ray diffraction pattern of the powder X-ray diffraction pattern of the hydrated crystal form of the type [of lopinavir 7# containing about 90 molecules of water per molecule of lopinavir Figure 1 shows a 2 C nuclear magnetic resonance spectrum in the solid state at a frequency of 100 MHz for the type 1 hydrated crystalline form of lopinavir It contains about 8 molecules of water per molecule of lopinavir (Ve). Type 1 lopinavir contains about 0.8 molecules of water per molecule of lopinavir. Figure ¢: The mid infrared spectrum is housed according to the solid-state Fourbier transform of a hydrated crystalline form of type ] lopinavir contains about 5 molecules of water per molecule of lopinavir. The NMR spectrum of ©" in the solid state at a frequency of 100 MHz demonstrates the highly hydrated crystalline form [type] of jlopinavir. Significantly hydrating type 1 lopinavir (YYo).

Figure A: The mid-infrared excited spectrum (LY) of the Fourier transform in the solid state of a highly hydrated crystalline form of the type ! For -lopinavir Figure 1: The mid-infrared spectrum shows the Gy Fourier transformation of 0 solid state for the hemisolvate crystal form in isopropanol type 11 of lopinavir Figure 01 - : Show the mid-infrared spectrum ly of the Fourier transformation in the solid state of a solvate crystal form isopropanol 1500008001 type 11 of lopinavir contains about IY of 01 solvent by thermogravimetric Thermal gravimetry Figure 11: The mid-infrared spectrum (Wy) of the Fourier transform in the solid state of a semi-solubility crystal form in ethyl acetate of type 11 of Jlopinavir is shown. Figure VY: The spectrum of rays is shown middle infrared ly of the Forbier transformation in Vo solid state of the soluble crystal form in ethyl acetate type 11 for lopinavir containing Ji of 4.0 mole of ethyl acetate per? Mole of lopinavir by thermogravimetric measurement. Figure 11: The mid-infrared spectrum, Gy, of the Fourier transformation in the solid state of a semi-soluble crystal form in chloroform of Y. Type 11 of lopinavir - lopinavir. Figure Ve: The infrared spectrum is shown. The near-infrared Gy of the Fourier transformation in the solid state of a semi-dissolvable crystal form in isopropanol of type 11 for lopinavir Form Yo: The near-infrared spectrum Gy of the Fourier transformation in the solid state of Yo of the form Dissolvable crystal in isopropanol type II

Lopinavir 7 | It contains about 77% of solvent by thermogravimetric ratio. Figure 11: The near-infrared spectrum, Gig, of the solid-state Forbier transformation of a semi-solubility crystal form in ethyl acetate of type 11 ° is shown for lopinavir. Figure 117: The near-infrared spectrum is shown Wy for solid-state Fourier transformation of soluble crystal form in ethyl acetate type 1! For lopinavir containing less than 15 moles of ethyl acetate per ¥ mole of lopinavir measured Thermal weight. + A: The near-infrared spectrum appears according to the Fourier transformation in the solid state of a semi-soluble crystalline form in chloroform of type A [for lopinavir] Figure Ya: The mid-infrared spectrum appears, Gy For the solid-state Forbier transformation of the soluble crystalline form in ethyl acetate of type Vo 1 for lopinavir +10010871. Figure Ye: The near-infrared spectrum, Gy, of the Fourier transformation in the solid state of the soluble crystal form in ethyl acetate type 1 of lopinavir is shown. Figure 71: The mid-infrared spectrum is shown. Gay Fourier transform in Y. The solid state of a desolvated crystal form of type 1 for lopinavir Figure YY: The near-infrared spectrum of the Gay fourier transform in the solid state of a desolvated crystal form Soluble type 111 of lopinavir (vy form): The X-ray diffraction pattern of a powder of the eluted crystalline form Yo is shown. Soluble type TIT of lopinavir (YYo)

Figure Y: Cada harbors the NMR of ©" in the solid state at a frequency of 100 MHz for the type 111 eluted crystalline form of lopinavir. Figure Y: Thermogram of a differential scanning calorimeter differential scanning calorimetric (DSC) thermogram ° for the type 1 insoluble crystal form [of lopinavir] YT form: the mid-infrared spectrum is based according to the Fourier transform in the solid state of a non-solvated crystal form Type IV for lopinavir 10871:2M10. For a powder of the type IV non-soluble crystal form of lopinavir in the form Ya: the NMR spectrum of “©” in the solid state at a frequency of 0 MHz Vo of the type 17 non-soluble crystal form of lopinavir .lopinavir Fig. FL : differential scanning calorimetry (DSC) thermograph showing a type IV non-melting crystal form of lopinavir lopinavir Fig. TY: showing the X-ray diffraction pattern of a powder of the solvation crystal form In 7. Ethyl acetate type 1 [for lopinavir] Detailed description according to the invention Raman; Novel crystal forms of (SY SY) 88)-1-(7;+7-dimethylphenoxyacetyl)amino-7-hydroxy-TV)TY)om(7))-7-methyl tetrahydropyrimidonyl butatoyl)amino-A-1-yo-phenylhexane (28,38,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-Yyo)

A

(lopinavir (2-(-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane -(lopinavir lopinavir) In one embodiment of the present invention there are hydrolyzed crystal forms of lopinavir, and for the purpose of distinction reference is made to the crystal forms The rehydrated type 1 crystalline forms contain from about 5 molecules of water per molecule of lopinavir to about ?molecule of water per molecule of lopinavir. Purification or Te sll The hydrated crystalline forms of lopinavir separation ©1008 during the final steps of the lopinavir preparation process 1000787 and in lopinavir the process of preparing pharmaceutical compositions to give lopinavir, which contains about lopinavir, and the hydrated crystalline form is of the type ! Therefore, unless a molecule of water per molecule of lopinavir 8 is preserved in lopinavir of approximately zero #, the crystalline form has a relative humidity of relative humidity (relative humidity conditions) a molecule of water per molecule of 155 Type | lopinavir 10010807 contains more than lopinavir M1 lopinavir and, if dehydrated, the hydrated crystalline form of lopinavir type 1 <lopinavir to an amount of less than about 0.89 water molecules per molecule of lopinavir 0 amorphous . lopinavir obtains lopinavir, which contains lopinavir, while the crystalline forms of the type | for lopinavir and about? 1 molecule of water per lopinavir 1 molecule of water per molecule of lopinavir © solubility eld cw ll lower range and upper range; fopinavir a molecule of hydrolyzed lopinavir type 1 crystalline; However, lopinavir observed for solvation +20 forms of lopinavir The water content of the crystalline form may vary within this range depending on the temperature and water content of the surroundings of the crystalline form. The term 'highly hydrated crystalline form [hydrogenated crystalline form of lopinavir type]' is used in this statement to refer to lopinavir forms of water per molecule of lopinavir: 16008 to about 15 containing more than Preferably; contains ley + ?1 molecule of water per molecule of lopinavir vo

The highly hydrated crystalline form is of type | for lopinavir from about 0.75 to about 1.4 molecules of water per molecule of lopinavir and better; The highly hydrated Type 1 crystalline form of lopinavir 10808 contains from about 0.01 to about VA molecules of water per molecule of lopinavir °C and in a preferred embodiment; The hydrated crystalline forms of lopinavir: 8M10 are of the type ! intrinsically pure For other forms of dopinavir including the amorphous forms; solubility Non-soluble forms from which the solubility has been removed. It was found that the mid-infrared spectrum, Gi, of the Fourier transformation in the solid state is a means to distinguish the hydrated crystal forms of Te sill of lopinavir 100108712 0 and to differentiate the hydrated crystal forms from other crystal forms of lopinavir 100708718 and the hydrated crystal forms of the type ! for lopinavir 10010408 (La) including the dehydrated crystalline forms of lopinavir: M of type | intrinsically pure) mid-infrared bands f”: 010-010 according to the characteristic solid-state Forbes_transformation shown in Table 1. Table 1 shows the range of peak positions for each of the infrared ys bands The characteristic average of seventeen in the mid-infrared spectrum according to the Fourier transform in the solid state of the type 1 hydrated crystal forms of lopinavir. This indicates that any type 1 hydrated crystal form of lopinavir has a peak at a position within the range ( The most characteristic of the type 1 hydrolyzed crystal forms of lopinavir (including the substantially pure | type 1 hydrated crystal forms of lopinavir) is lopinavir in the mid-infrared bands Woy of the Fourier transformation in the solid state of the carbonyl elongation in the amide bond. vo type 1 of lopinavir, and any hydrated crystalline form of the type! for lopinavir

Vo Including the hydrophilic crystalline forms of lopinavir of the type ! substantially pure) peak Ly) 111 and a peak at a site within the range Taw 1157-1187 at a site within the range 1 _ © cm 11 Yo (including the hydrated 1 crystalline forms of the type lopinavir and characterized Forms of lopinavir also with a peak specific to purified type 1 rehydrated rays (Loan 454! lopinavir lopinavir °

Infrared TYVA of samples in the solid state at a location within each of the ranges. yl sr 14-716 cm A 6417 la sed "and// a-7 la cm 1 gibdol Ranges of positions of peaks in the mid-infrared ranges according to lopinavir solid-state Forbi transform of type 1 hydrated crystal forms of lopinavir Minimum Maximum Strength cm 1- Weak/None Yo.o vedo Strong/Medium Strength 1 77171 Medium Strength 74 78 Weak ERE: ¥.oA Weak Yor) Yove A Medium 18 Weak 17 vary Weak YAYo Metkha la Strong 117 017 Strong/Medium Strength 10110 1.01 Strong 111 YoY Medium Strength 11 Yio. VEY, L Medium Strength YY "9.6 A 0 Medium Strength Medium 016 1014 Weak 01 01

YYo)

1 The crystal form of lopinavir 10010218 has a type 1 crystal form that contains about 1 molecule of water per molecule of lopinavir 7 has an X-ray diffraction pattern [8] The crystal form of lopinavir and the lopinavir .1 powder form shown in the figure Spectrum of lopinavir containing about 0.8 molecules of water per molecule of lopinavir m 6" L NMR in solid state; near-infrared Fourier-transformed spectrum and Fourier-transformed mid-infrared spectrum where (a and ;; appear in order. The sample from which 9 oY obtained these spectra in the figures on infrared and NMR spectra could contain more than 0.9 molecules of water per molecule of lopinavir to To some extent due to the hygroscopicity of the crystalline form about 0.8 molecules of water per molecule of hydration 4 wall Au level when yy, -lopinavir lopinavir and the angle positions (07) of the characteristic peaks in the X-ray diffraction pattern For a powder of the hydrated crystalline form of type !lopinavir: 100108 which contains about (including lopinavir forms of lopinavir) 0.0 molecule of water per molecule of lopinavir of the hydrated crystalline type ! Intrinsically pure containing about 8 molecule lopinavie yo

CoN x V,Yo 1 as shown in the figure (lopinavir of water per molecule of lopinavir

COV ETYEVT SOY SOY EY gn Coy + M Co Tay Soy gy 01

SOY EYE HELP AND YA JAR VE THE HYDRATE CRYSTAL OF THE TYPE ! Which contains Topinavir The form of lopinavir Ye lopinavir can be prepared from the form of lopinavir at 0.5 molecules of water per molecule of lopinavir, a molecule of water per molecule of 1,5 hydrated crystalline type 1 containing more than by removing water at zero relative humidity. if lopinavir continues; half-life lopinavir; Lopinavir A”ail gets the process of removing water beyond the crystalline stage.

YYo)

1 of a solution or lopinavir The hydrated crystalline form of type 1 of lopinavir can be prepared in water or from solutions in mixtures of water and organic solvents as an ALE miscible suspension that is miscible with water. Examples of organic solvents include organic solvents and the like; and in mixtures of water and acetonitrile soluble organic solvents from 158 m acetonitrile by volume to about 701 m miscible with water; The amount of water can vary from about preferred method; (By volume) 00 to about 7500 vol (preferably from about 7500 vol) can be prepared by crystallization by crystallization of lopinavir a highly hydrated crystalline form of lopinavir type 1 followed by hydrated cethanol in warm solution In a mixture of lopinavir water and ethanol, prolonged exposure to a high relative humidity environment. 1000891 via or 7718 at elevated RH (eg, at an RH of about more than lopinavir). The pattern is lopinavir and the highly hydrated, type 1 crystalline form of lopinavir is in the case BC X-ray diffraction of powder and NMR spectroscopy of L for Fourier-transformed solid and Uy-solid; near-infrared spectrum for Fourier-transformed solid, where each shows Gly in the mid-infrared and + in order. 7 ce in the figures for the characteristic peaks in the powder X-ray diffraction pattern (BY) and the Ye corner positions (including the lopinavir form) are of the highly hydrated Type 1 crystal form of lopinavir As indicated in lopinavir for lopinavir Gos ga highly hydrolyzed crystalline pure type 1 + Rflar Ae Sey female Clara Tee female x E: Ham JS + M30 Cu VAY Co Female 4 F + Female Karak, Female for Farql

SOV EYNVE Ra and ve

YYo)

VY

The highly hydrated crystal form of type 1 intrinsically pure lopinavir (67) is characterized by peaks in the powder X-ray diffraction pattern that have angular positions. (lopinavir for lopinavir, £400, 4 p.a., p.a., p.a., p.a., p.t., te JAN, as indicated in a a x et CU) RAD L ave Soy ££ mr Su) Ve X-rays and details of the experiment WS Media for single crystal lopinavir for the highly hydrated crystalline form type | ) =a network media 1,445 angstroms (;) =b , 10,7771 angstroms (8) <>

Vio, eo (1) angstrom' YEVEY (8) = V (0) C2 Space Group

A 7 value Calculated density 4 g/cm" pail Bruker SMART measurements Angstrom diffractometer 020117 -3 Mo Ka Radiation Temperature Ambient temperature £ 1,1 Maximum OY

Lorentz-polarization Correction Lorentz polarization 77745 Number of reflections measured Grand total: Structural solution and improved figure

OFA (1) o 0 > 1) Number of Observations 77 Number of Variables 8.77 Reflections Ratio/Meaning

GAYA Ladan Ry ¢R Leftovers: —_— Ru 8 Leftovers:

Ve and in two further embodiments according to the present invention are solvation crystalline forms of lopinavir ©10871m10. Depending on the X-ray determination of the single crystal structure; The first embodiment of lopinavir 108:00 dissolvable crystalline forms includes a crystalline structure in which aggregates are held together by mutual interactions between lopinavir bonds of short lopinavir molecules. The crystallographic axis is not arranged along the crystallographic axis, hydrogen °, but simply fills <hydrogen bonding. The solvent molecules play a role in the hydrogen bonding, the cavities that exist between the aggregates of lopinavir 1001088 molecules.

AL of this embodiment with type Gg 100108 » Solubility crystal forms of lopinavir and based on X-ray determination of the single crystal structure; The second embodiment includes the 8m10 lopinavir solubility crystal structure with a crystal structure in which the lopinavir molecules are bound and the sheets of lopinavir molecules are hydrogen bonded in curls as hydrogen bonded M0:#7 sheets; producing channels occupied by different amounts of molecules for the second embodiment of the solvent Tidy shapes. The solvent molecules do not play a role in the hydrogen bonding of lopinavir crystalline solubility. for the purpose of discrimination; Topinavir [1] forms of lopinavir are referred to for this embodiment as solubility crystalline type Gag 1 [1] type Useful for purification or separation of topinavir Soluble crystal forms are type 1! of lopinavir.10010871 : During the final steps of the lopinavir preparation process, lopinavir is particularly useful, and the soluble crystalline forms of type 11 of lopinavir are considered to be one of or contain very small amounts of JA crystalline lopinavir to obtain lopinavir > lopinavir During the preparation process of lopinavir pan a different group of impurities that gS and form the type 11 solubility crystal forms of lopinavir 108108018 half of the crystal there are two molecules of asymmetric unit per asymmetric unit os AT usually. In the words lopinavir: 100808 and one molecule of the solvent. Lower solubility levels are also possible. 1! The soluble crystal of the type topinavir is a form of lopinavir Ui ja and the solubility can be removed vo

Vo is that; If more than heating in vacuum with heating and drying is removed by drying about 775 of the upper permissible limit of the solvent (where the upper permissible limit is the half-solubility); Lopinavir 108808 is obtained as an amorphous substance. Thus; The soluble crystalline forms of lopinavir of type 1 contain from about 0.176 molecules of solvent per molecule of .100108712 to about 0.5 molecules of solvent per molecule of lopinavir. The solubility of type 1 [organic solvents] is relatively small. It includes a number of polar organic solvents, polar isopropanol en-propanol p--propanol cethanol methanol bud ¢t-butanol ciso-butanol iso-butanol n-butanol p-butanol isopropanol th-pentanol 150-2071 alcohol iso-amyl alcohol p-amyl alcohol ye tetrahydrofuran acetone acetone cethyl acetate acetate Ethyl t-pentanol glycol methylene chloride chloroform chloroform ctetrahydrofuran dimethyl sulfoxide ketone methyl ethyl ketone cpropylene glycol dimethylsulfoxide and the like

Ig sill soluble crystalline topinavir and in a preferred embodiment the vo forms of lopinavir are the hydrolyzed forms; Ly os AT jopinavir ling for pure amorphous Goa ga forms; other soluble forms; non-solubility forms From which the solute was removed. For the Fourier transformation in the state Gy, and it was found that the mid-infrared spectrum!] The solid lopinavir crystalline form is a means to distinguish lopinavir forms. 17 About lopinavir_Go, ©: mm1 other crystal forms. The 0m10 lopinavir type 1 solubility crystal forms (including the substantially pure lopinavir 1001081 type 1 solubility crystal forms) have infra-bands of the Fourier transform In the characteristic solid state shown in table iy the mid-infrared The table shows the range of positions of the peaks for each of the mid-infrared bands vo

YYo)

1 for the eighteen distinct Gy-Forbier shift in the mid-infrared spectrum in the solid state of lopinavir +1 solubility crystal forms of type !1. This means that it has a peak at a location within the range (the lopinavir limit for any solubility crystal form type 1! for lopinavir .7 the highest to the minimum) for each of the peaks shown in the table, the solubility crystal form of the type Jopinavir is The most characteristic of lopinavir forms > Solubility crystalline type 1 [essentially pure) in lopinavir Including lopinavir forms Ly) 1 Fourier transform in the solid state Gy Locations of the mid-infrared bands These bands fall within The amide ranges in the carbonyl amide bond of the carbonyl elongation of the lopinavir_forms Tas 117-19 Sama 1107-6 cm and 1177-1171 solvation crystalline lopinavir p«omh1 solubility crystalline type 1 and any form of lopinavir has 0 type 1] (including lopinavir: 0m: pure type 11 solubility crystal forms Peak at within range (Tan 1177-1151) Peak at within range (Gass)

Cam 1179-1119 and a peak at a location within the range Taw 1107-05 Dissolvable crystal forms of lopinavir 8 are also distinguished from the type!! (including substantially pure Type 1 soluble lopinavir »02M forms) with a peak specific to ye -776 infrared rays for samples in the solid state at a location within each of the ranges. 7 to VoA-viy to VoA-viy

Vv

Y gybdol _— ada amplitudes of peak positions for mid-infrared bands according to 1] lopinavir solubility crystal of solid-state Fourier transform of lopinavir sell forms lower limit upper limit y= 1 — _— Aaaaaaaaaaa Medium rive Lenny Medium Strength 79796 7", Weak Your L 7 Weak Medium 47 111 Weak 1 7157 Weak YAYA YAH Strong 1 YT AA Strong Vito fas Powerful 74 "4 Medium Power 00 106 HP 117 116 Medium Power 104 Vio. Medium 177 VEYA Medium 4 VY. gall Medium 117 111 Moderate 6 014 Weak 07 Veto ee —— ee —— Fourier transform in the Gy state The mid-infrared spectra show the Type 11 solubility crystal (isopropanol lopinavie lin JAY aula) 4 01 In the forms (chloroform and chloroform ethyl acetate ethyl acetate < isopropanol) and the near infrared spectra appear according to the Forbes transform in the case AY and 17 110e crystalline solubility of type [] (isopropanol lopinavir solid forms Lupinafer V ve in the forms (chloroform and chloroform ethyl acetate ethyl acetate “isopropanol

AA SY followed

Ya

Soluble crystal type 1! by topinavir. Solid forms of lopinavir can be prepared in excess in the solvent and allowing the suspension to stabilize with the passage of time. From topinavir, the soluble crystalline filtration of type 11 lopinavir is suspended by lopinavir filtration, and then the soluble crystalline form of lopinavir type 11 is separated from lopinavir. Forms of lopinavir can also be prepared in the solvent; lopinavir from supersaturated lopinavir solution by cooling a supersaturated solution and then separating the form of lopinavir seed crystals (dil) with or without type 1 solvation crystal [1] by filtration. 7:

AULT solubility crystalline type Topinavir Slow solvent forms of lopinavir can also be prepared from a solution of lopinavir 10078 and then the evaporation form of soluble crystalline type 11 is separated by filtration. Topinavie 0!] Crystalline lopinavir The solubility of the type Jopinavir Lad forms of lopinavir can be prepared in the solvent; Then, lopinavir: 1008, the soluble crystalline type, was separated by filtration. Z and the media for the single crystal as determined by X-rays and the details are the semi-solubility crystalline Vo in ethyl acetate Topinavir related to the experiment for the semi-solubility crystalline form of lopinavir in chloroform [type lopinavir] and the form of lopinavir (ethyl acetate of the type 1 as follows: chloroform

1 Single crystal media as determined by X-rays and experimental details of a figure

Ig sd of ethyl acetate half-soluble in ethyl acetate lopinavir Experiment details Crystal data Monoclinic crystal arrangement 1.757 angstroms (1) =a Grid media 77,490 angstroms (Y) = p 9.8541 angstroms (7) = ¢

AAT (1) angstrom s - 7794, (V) = v (4 = aad)) P2, spatial group 3 2 value of mass 1.1 A Calculated density Intensity measurements

Bruker SMART 1.9201 -72 angstrom diffractometer Mo Ka exposure temperature ambient temperature ey maximum OY correction Lorentz polarization

VEAYE Number of reflections measured Grand total: 57111 Singular: Structural solution and improved form (£41) ((I) 6 5.0 > 1) Number of observations

AAY Variables dae 84 Reflections Ratio/Mean 4 46 Ry Raid J gall -_— 0 Bw RAs dell

Single crystal media as determined by X-rays and experimental details for lopinavir 7 semi-solubility crystal form in chloroform type IT: Experimental details AAA AAA —_- Crystallographic data The orthorhombic crystal system Network media and < (01) 1,79707 angstroms (FYE) (Y) =b angstroms VY EAVE (1) = ¢ angstroms YVEQA (TV) =v angstroms Space group 2i (number - YA) Z value Calculated density 7 Tanai Intensity measurements Bruker SMART diffractometer Mo Ka gly! (3- 7110 angstroms) Temperature OY ambient temperature Maximum correction Lorentz polarization Number of Measured Reflections Grand Total: 144560 Singular: 4759 sae Observations (I) 6 0 > 1(7) Number of Variables 778 Reflections Ratio/Meaning and Substances | Residual Residual: Rw 'tR p 5 0 11 HO Substances Bw Rand —_- Type 111 The type 1 soluble crystal forms of lopinavir are useful for the purification or separation of lopinavir during the final steps of the lopinavir preparation process. The solubility crystal forms of Type 1 lopinavir is particularly useful for obtaining lopinavir that is crystalline during pregnancy or contains trace amounts of faa

From a different group of impurities produced during the preparation process of lopinavir 1001187 and the solubility crystal forms of type 11! Lopinavir: 108780 are thermodynamically stable crystal forms separated from solvents that generally include solvents

° No Calli hydrophobic organic solvents or solvents too large to fit into the crystal lattice of lopinavir type 1 solubility crystal forms! Type 1 solubility crystal forms of lopinavir contain solvents that include p-hexanol. n-hexanol p-octanol 3-ethyl-3-pentanol ?-?-licha-0 n-octanol polyethylene glycol acetate cethyl acetate (Ji) isopropyl acetate ‏

lid Ve n-butyl acetate sglycerol triacetate acetone methyl isobutyl ketone 7 4;-dimethylpentanone “2,4-dimethylpentanone alpha- Tetralon (ie calpha-tetralone methyl t-butyl YY ether 4 4-tetramethyl tetrahydrofuran 08 5 8 })(¢2,2,4,4-tetramethyltetrahydrofuran diisosorbide cisosorbide dimethyl ether Jil Jie Toluene ©«P:01» stetralin

Vo nitrobenzene para-xylene ep-zylene sulfur because “sulfolane hexane chexane heptane 8m decalin and oleic acid and the like.

In a preferred embodiment; The 10:08 solubility crystal forms of Tg lopinavir are substantially pure relative to other lopinavir forms; including hyphae; amorphous other solubility forms; Non-soluble forms from which the solubility has been removed.

1 It was found that the mid-infrared fiber Gy of the Fourier transformation in the solid state is a means to distinguish the solubility crystal forms of lopinavir from Mg sil and to differentiate lopinavir 875: m1 soluble crystal forms of type 117 from lopinavir_ forms

:: than other crystalline.

The solubility crystalline forms of Topinavir type 1 (including the substantially pure solubility crystalline forms of Topinavir type 1:10108) have infrared bands.

Yy 7. The mid-infrared according to the Fourier transform in the characteristic solid state shown in the table. The table shows “the range of positions of the peaks for each of the mid-infrared bands of the fourteen distinct Fourier transform in By in the mid-infrared spectrum Solid state lopinavir ©0891TM»E1 solvation crystal forms of type 111. This means that any type 111 solvation crystal form of lopinavir has :10010871 a peak at a position within the range (0.7 .7 bound lower to upper bound) for each of the peaks indicated in the table

MI solubility crystal forms of lopinavir The most characteristic of substantially pure !11 solvation crystal forms of lopinavir (including solid-state Fourier transform lopinavir forms) are the infrared band locations. The intermediate red -16595 is located within the amide range of the carbonyl amide bond, the carbonyl elongation is 0, and repeatedly; the solubility crystal of topinavir type LIT is located 7 cm for the lopinavir solubility crystal forms fopinavir 7 cm The VTEV-VITT forms of lopinavir have a second domain within the range

VU type 111. However, in some cases; The second band (in range cm') appears as a shoulder on band one or is not sufficiently separated from band 17 of lopinavir I to be recognizable as a second band. Any lopinavir ve type 117 form (including substantially pure !11 solubility crystal forms of lopinavir »1108 type 11) has a peak at a position in the range 1137-1155 cm"; it may also have a '.' cm 1147-1577 peak at a position within the range of solubility crystalline type 11 [including topinavir and substantially pure! X-ray peak ©

Infrared TYVY of samples in the solid state at a location within each of the ranges 47 cm A-7-L name A. YY ova 1 cm A for the characteristic peaks in the powder X-ray diffraction pattern (BY) and the corner positions are Lopinavir IE gl ge (ethyl acetate of the soluble_crystal form (in ethyl acetate)

HI of ethyl acetate (including the soluble crystalline form) in lopinavir ve

Substantially pure lopinavir (lopinavir as shown in Figure YY blood" + L LOY yey Co d anth Cy YATE TAY 4 dome ar and qa + Jon table ¥ oo - - wo }. SM SM SS Sanad Masala 46 m Strong Y FYVA F Medium Strength Yo 71 Weak TY N Weak Yao 16 Medium 7" 1174 Weak YAVY YAoy Weak 15 A Strong 07 fan 117 Strong No Yoyo Strong You) 0 Medium Strength Véoo Yeo. Medium Gall 5 1 We Medium Strength 17 17 Medium Strength 1 0 4 1 0 9 0 Weak 017 Veo Medium AA —_- o

AR

For the Forbes shift for samples in the Gy state, the mid-infrared spectrum of the soluble crystalline ethyl acetate type appears in the solid ethyl acetate Topinavir for the form of lopinavir, and the near-infrared spectrum appears according to the Forbes shift for V8 samples in Figure 1 ethyl acetate, the solubility crystal of lopinavir ethyl acetate, in the solid state of lopinavir form .01 M. of type 11 in the solubility crystal form of type 1!] by Jopinavir, and forms of lopinavir can be prepared The excess solid in the solvent and allowing the equilibrium of the suspension with the passage of time. lopinavir Suspension of soluble crystalline lopinavir of type 11 by filtration. Then, the soluble crystalline form of lopinavir of type 11] is separated from Topinavir. Forms can also be prepared lopinavir in the solvent; With or without the addition of lopinavir by cooling a supersaturated solution of lopinavir 0 solvation crystalline lopinavir and then separating the lopinavir form. 5680 crystals skill .5680 crystals start leaching. [11] By making lopinavir available, forms of lopinavir can also be prepared by slow evaporation of the solvent from a solution of lopinavir: 1001081. Then the soluble crystalline form of lopinavir of type 1 is separated by filtration. lopinavir - 0

Hg sid) The soluble crystalline forms of lopinavir: 10008 can also be prepared from in the solvent; lopinavir slowly to a heated solution of lopinavir antisolvent by adding an antisolvent

HI is a soluble crystalline form of lopinavir and thus induces crystallization. Then the lopinavir form is separated by filtration

Yo Media for the single crystal as determined by X-rays and details of the experiment: HMI of the type ethyl acetate crystalline soluble in ethyl acetate lopinavir of the form of lopinavir Details of the experiment Crystallographic data The crystalline system is biconvex straight 3,451 Angstrom (2) =a Network Media Angstrom YV,0A (1) =p 11,577 Angstrom (4) = ¢ Vay (e) =v (01 =a) C222, spatial group

A Z is the value of the intensity measurements

Rigaku AFCSR AFC5R Slay Angstrom diffractometer (094174 -7) CuKa Irradiation Temp Ambient Temp 0 Max OY

Lorentz-polarization Correction Lorentz polarization (Vem AY) Absorption (Transition factors: 26570) Number of reflections measured Grand total: 159718 Singular: Osan Structural solution and Figure 718: (6) (0 > 1) Number of observations Number of variables 1 Reflections ratio / median

GeV 3 Ry ¢R Remaining: of gall -_— o RwR Remaining: dd

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Yi

An example of an insoluble crystalline form of type 1 was prepared for lopinavir from acetonitrile. It was not possible to prepare a crystalline form of type 1!

(JC, Complete to lopinavir: M1 from all other solvents. The eluted crystalline form of lopinavir is of type 1!] Take in purification or

M chapter of lopinavir: 087 and in the preparation of pharmaceutical formulations for administration of lopinavir «10010877. It was found that the mid-infrared spectrum according to the Forbier transform of samples in the solid state is a means to distinguish the UI-type desoluble lopinavir form and to differentiate the 117-type de-soluble lopinavir crystal forms from the other lopinavir: 1010 crystalline forms” except The solubility crystal form is of the type !11.

01 The eluted crystalline form of lopinavir type 1!] (including the substantially pure eluted crystalline form lopinavir type !11) has the mid-IR bands according to the Fourier transform of the characteristic solid-state samples. shown in the table.” Table ¥ shows the range of peak positions for each of the 16 distinct mid-infrared bands in the Gy-shift mid-infrared spectrum

HEE sill crystalline desolate form of Topinavir FOURBIET for solid-state samples of the lopinavir form yo This means that the 11 mm1 form of lopinavir form 1: has a peak at 7. position within the range (minimum to upper limit) for each of the peaks shown in the table

The most distinguishing characteristic of the type 1 desoluble M1 lopinavir crystalline form (including the substantially pure Type 1 desoluble lopinavir 1000871) x, is the positions of the mid-infrared bands ta of the Forbier transform of samples in the state Solid for the carbonyl elongation in the amide bond and a range is within the range 1137-1505 cm ' for the lopinavir + eluted crystalline form of type AEE and frequently a second band appears (in the range 1147-1717 cm ') in the form of a shoulder on the first domain or is not sufficiently separated from the first domain for SUL to distinguish as ve a second domain. Any form of lopinavir + soluble crystalline type 11 (including

Yv (essentially met) a peak at the soluble crystalline IIT of the type Topinavir that is the form of lopinavir located within the range 1177-1185 cm ' it can also have a peak at a location within the range cm in the form of a shoulder on the peak at Location within range 1147-1

Caw 1117-1108 for the Fourbier transform of samples in the state of Ga and the mid-infrared spectrum shows .?1 de-soluble crystal of type 11 in the solid form of opinavir for the form of lopinavir for samples in the solid state of ag yg The near-infrared spectrum is shown according to the shift. The YY crystalline desolate form of type 11 is shown in the figure. cli Pc type 111 is shown in Fig. 77. The NMR spectrum of the eluted crystalline 0-0 MHz topinavir of the solid 0-0 form of lopinavir at a frequency of [type 11] is shown in Fig. 4 7. The thermograph is shown Differential scanning calorimetry for the form of lopinavir

Yo crystalline elusive type 1 lopinavir in Figure 7 showing a differential scanning calorimeter thermogram of the lopinavir form of lopinavir represents heat absorption upon fusion with crystalline elusive glycoside type 117 lopinavir 1 (Vg joules/g YA Um (1 has - AA and a peak at (Celsius) a starting point at 15 m (°C up to AE) when we perform a differential scanning calorimeter heat measurement process with a scanning rate reaching a temperature of 10 m for a sample that has lost zero of Its initial weight when heated to

Ady at a rate of a 84 and angle positions (07) of distinct peaks in the X-ray diffraction pattern of a type 1 eluted crystalline Ye powder (including the eluted crystalline form Topinavir type 1 lopinavir [ 11 met substantially) as indicated in lopinavir with a female “no female for another hot Cus” as follows: Mia YY Figure COVEY Dabeth Frik LR and TY Evy Danth Lahre Jarre

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Ya

the eluted crystalline form of lopinavir and better; Pure Topinavir Type 111 (including the lopinavir form)

CA) with the presence of peaks in the powder X-ray diffraction pattern having corner positions (Gass Arla Ajart Cy TUR) ?? as follows; Mouth P JS as shown in Faraj Jar Sone vw for Khalral Art Soy err. Cag mm 0

TET EY Female TA Far + R and Radabat. f 1 + Yy , v1 and single crystal media as determined by x-rays and details of the experiment

Hg sill The eluted crystalline form of lopinavir of lopinavir —_—_— a a a aa aa aa rm Experimental details —_—— A es aa aa Crystalline data straight (AT ea Crystal system 7.0475 angstroms (01) a = lattice media 77.80 angstroms (VY) = b 115744 angstroms (1) = 11114 angstroms, (A) = V (01) group Stereotyping (22 (Issue

A Z The calculated density value is 1,100 g/cm A Measurements of intensity

Nonius Kappa CCD CCD LS Nonius Angstrom diffractometer 170177 -72 Mo Ka Radiation Temperature Ambient Temperature 1 Maximum BY 784914 Number of Measured Reflections Grand Total: 51467 Singular: Structural Solution and Optimized Form 4 (0) oY, > 1) Observations sae No. of Variables z 4,7) Reflections Ratio/Meaning

IVY Meb Rw ¢R Materials Remaining: _— Rw Raid Materials

Ya crystalline lopinavir of the present invention exists the soluble form of lopinavir Gy Lad and in another embodiment the non-dissolving crystalline lopinavir according to lopinavir is referred to as the non-dissolving opal form of lopinavir. And for a purpose

IV of this embodiment by type in the purification nda fopinavir of lopinavir TV The non-soluble crystalline form is considered to be of the type lopinavir and in the preparation of pharmaceutical compositions to give lopinavir or to separate the non-solubility crystalline lopinavir 0 of the type lopinavir In a preferred embodiment; Forms of lopinavir, including clopinavir, are substantially pure relative to other forms of the 7-agonist lopinavir; amorphous solubility forms; Other insoluble and insoluble forms. Fourier transform of samples in Gy It was found that the mid-infrared spectrum gs solid state is a means to distinguish the insoluble crystal form of lopinavir 101081 from ve and to differentiate the insoluble crystal form of type 17 For other crystalline forms TV .lopinavir of lopinavir (including IV and the non-solubility crystalline form of lopinavir 1001088 is of the intrinsically pure type) IV bands of lopinavir 10010891 non-solubility crystalline form of the infrared type - The average according to the Fourbier transform for samples in the characteristic solid state shown (yo under da SY) in Table 4. The table is shown; The range of locations of the peaks for each of the 19 distinctive mid-red bands in the mid-infrared spectrum according to the non-solubility crystal Fourier transformation of lopinavir type for samples in the solid state of the non-melting crystal form lopinavir type 17 peak lopinavir This means that it has any form of IV lopinavir. 4 at a location within the range (lower to upper limit) of each of the peaks shown in Table © and when the mid-infrared spectrum of samples in the solid state is obtained at a resolution of ; poison '. A peak may also be observed at a location in one or more of the (strong) Tan 1137-17 following additional feature ranges: 1774-1354 cm' (strong); This would be Gay (strong). and at a higher resolution; or after removing the lattices Tam 1140-7 additional vertices are recognizable. vor r.

The most distinctive feature of the type 7 non-solubility crystalline lopinavir form (including the intrinsically pure Type 17 non-soluble lopinavir 0108M crystalline forms) is the positions of the mid-infrared Gig bands of the Fourier transform of solid-state samples of the carbonyl elongation carbonyl in the amide bond and these ranges fall within the m0 ranges 1188-1186 cm and 17-1176 cm' for the non-solubility type Iv 8m10 crystalline form of lopinavir 8. In addition and especially at higher resolution; The ranges are in the ranges 1174-1174 cm 1117-15 cm" and 1148-1747 Tam + and any lopinavir 10008 is a type IV non-soluble crystal form (including the 08mm1 non-solubility crystalline forms of type IV) intrinsically pure) a peak at a location within the -_ range 1180-1586 Tan and a peak at a location within the range Ta 1170-1178 as it can also have a peak at a location within the range 1175-1718 cm ' and a peak within the range

Non-solubility crystalline type 17 (including lopinavir) and a peak within range 1144-19647 cm and a peak within range 1117-11. The form of lopinavir is also distinguished by the substantially pure non-solubility crystalline form 17 lopinavir 10008. ) with an infrared peak for samples in the solid state at a location within each of the ranges 45-780 / cm a yo

764-/1 for the noun or 745-5) for the noun '.

A

Table; _— The ranges of the positions of the peaks for the mid-infrared bands according to the Forbes transform of solid-state samples of lopinavir crystalline non-soluble form of Vg sll lower limit upper limit sal 1-1 cm cm a 174 Medium Medium FEY vivo Medium 67 (EER M Medium Strength 7 F Medium 4 Medium 7 71 N Weak YAY MF Weak Medium 16 Y404 Weak Yary 7171 Weak YAVo YAY. Daha Ma Strong fas Strong yar. YiYo Strong Yor yoy ¢ Medium Strength Yeon 1001 Medium 0 Acker Medium 74 114 "74 Weak 4 4 Weak ‎ 01 "<4 _— er

AREA non-soluble crystalline 17-spectrum lopinavir is the solid form of lopinavir; a mean red lial infrared spectrum according to the cual Fourier transform of samples in the solid state; powder X-ray diffraction pattern; The Gig spectrum near the NMR of ©" for samples in the solid state and the calorimetry thermograph, respectively. For the characteristic peaks in the powder X-ray diffraction pattern (BY) and the corner sites are of type 7 lopinavir: 8M10 non-solubility crystalline form (including forms of

Oe as it is (Co ga, crystalline non-solubility of type 17, pure, topinavir, lopinavir, art, YVAN, anth Karh + art, AS, as follows: YA in the form

Sev R & A H E EA Cor made anth-claral 0 non-soluble crystalline formulation of Topinavir better. Lopinavir form

AE 17 insoluble crystalline form of lopinavir type 17 (including substantially (6Y) forms of lopinavir) having peaks in the powder X-ray diffraction pattern having angle sites Carachalp gel TAD as shown in the figure 14 as follows:

NEVE (Lahra Anth Qarfol Ar Co ETE Ce) Dr. Raqa Jared Tu EY ey Ark Aberth #Farahal Anth Ch) 5 VAL The differential scanning calorimeter (©050) thermogram of the shape of lopinavir represents Heat Absorption at Goby Usd 17 non-solubility crystalline form lopinavir (j/g) when conducting 7077°C = AH) melting with a starting point at 7111°C and a peak at m/min up to 1 degree measurement process Differential scanning calorimeter temperature with a scan rate of © temperature of 1960 m. Sigmoid and details Ae SVL The media for the single crystal as determined, non-solubility crystal type 17, are as follows: lopinavir Experimentally related to the form of lopinavir

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Single crystal media as determined by x-ray and trial details for the non-soluble crystalline form of lopinavir type IV lopinavir Trial details

Crystal data Crystal system rectilinear lattice modifiers (A) = 10.470 angstroms

YO XV (1) = b angstroms

¢ = (7) 5,777 angstroms

TYE (©) = V angstroms' stereogroup (number (01) value 7 ¢ calculated density Tafa 1 intensity measurements diffractometer AFCSR Slag rendering 0.9 41778 -3) Cu Ka, angstrom) temperature OY maximum ambient temperature YY correction Lorentz polarization

Absorbance (Transition factors: 493-8777 3) ax Measured reflections Frio: lle send Structural solution and improved shape Number of observations (I) o 0 > 1) a Number of variables 11 Reflectance ratio/median ¥en Remaining material: Rw ¢R father film

Yi from IV and the insoluble crystalline form of lopinavir: 10008 of the type can be prepared by slow cooling and slow evaporation of a saturated solution or by exposing acetonitrile to acetonitrile and in addition; Acetonitrile amorphous to atmosphere of acetonitrile lopinavir lopinavir with lopinavir acetonitrile crystals in acetonitrile lopinavir can be seeded with a solution of lopinavir to produce a larger amount of the form of lopinavir «0108»71H! Crystalline non-IV insolubility type 0

Soluble AV of the new crystalline type Jopinavir The following examples further illustrate the preparation of lopinavir forms of the invention. Room temperature in a mixture of lopinavir Prepare a saturated solution of lopinavir saturated solution at co. TB 50 ml of water and 0 ml ethanol at room temperature and slowly add 54 ml of water at a rate of Amounts to 0.015 ml/min using a pump. Filter out the resulting precipitate (crystals) by suction. cll After stirring throughout the syringe pump, inject 1 Example \o lopinavir Method for preparing a highly hydrated crystal form of type 1 of lopinavir

NMR tube A tube used in NMR measurements Le in lopinavir ml of water. Then add .+0 ml of a solution of lopinavir V, VO b very carefully (ethanol from Jaflopinavir 19 mg of lopinavir £AY, 19 mg) ethanol ethanol in the form of a layer extending over the surface waterproof upper. Cover the tube to prevent evaporation and leave it to remain undisturbed. And he obtained crystals of the Hydrated Crystalline type! For lopinavir 1 molecule of water per molecule of lopinavir 1.59 contains more than 7 days. Vo after about

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rs Example? lopinavir Method for preparation of a highly hydrated crystalline form of lopinavir type 1 ml of deionized distilled water 01 g of lopinavir ©1008 in a mixture of To 001 molar strength ethanol mL of 408 mL of ishaeol and deionized distilled water by gravity Call m. The solution was filtered 10 m by heating with moderate stirring at about floor to remove insoluble matter. The filtrate was slowly cooled with moderate agitation to The temperature of the mixture was at a rate of 1.50 ca ZB of the example product at room temperature, where it was sown at about medium at room temperature for three days. The resulting mixture was filtered under vacuum. Alba was transferred and any lumps were broken. filter paper The solid was filtered on a simple manual filter paper with a spatula 8080018. Then the solid was transferred to a glass crystal dish > over a saturated solution of chloride desiccator and placed in a glass crystallizing dish and after drying for 7 YO To maintain a constant relative humidity of sodium chloride and a relative humidity of 7978, about (m1 + TE) per day at room temperature obtained 1" g of the desired hydrated crystalline form of lopinavir 1010878. The diffraction pattern of 8 "© X-rays of the powder is shown in Fig. *. The NMR spectrum of .16 MHz is shown in Fig. 001 at a frequency of Adal for in-state samples.

Gs. Forbean transform for samples in the solid state in the form of Gly in the near infrared Forbean transformation for samples in the solid state in the form Ga The mid-infrared spectrum has a ratio of 74.7 as determined by the analysis volatile materials and the product contained Volatile substances LA thermal gravimetric analysis Y. Example; lopinavir Method for preparing a highly hydrated type 1 crystalline form of lopinavir lopinavir containing approximately 0 molecules of water per molecule of lopinavir mg of example product 9 in the sample holder of a diffractometer 001 approx. JT aa of sample and heated platform. The sample gall X-ray powder prepared with a controlled chamber vo i dry and nitrogen m/min maintained in nitrogen 1 atmosphere was heated to a temperature of 17 °C with a rate of hemihydrate on it at that temperature. And the conversion to the half-hydrate form was completed 1. The X-ray diffraction pattern of a powder in the Omg form takes less than 40-980 minutes. o The example contains about lopinavir m. lopinavir 1 molecule of water per 1 molecule of lopinavir 8 g of example product as a thin layer in a 1 Mercycian weighing cup Spread and dry overnight in a vacuum oven polypropylene weigh boat Ambient polypropylene. Gall were transferred at a temperature of Kilopascal at about -75 kPa, vacuum oven glass vials (lopinavir) the resulting hygroscopic product (half-hydrate form of lopinavir 0) and dried again for 7 hours at about -15 kPa at a temperature of The flasks were quickly covered with polypropylene caps and the anhydrous calcium sulfate resonance spectrophotometer was placed in an anhydrous calcium persulfate desiccator MHz in Figure 001 MN© for samples in The solid state at a frequency of Fourier transform for samples in the solid state Wag?. The near infrared spectrum of the Fourier transform for samples in Gy is shown in the figure. The product contained a volatile substance at a percentage of #7 as determined by thermogravimetric analysis. of isopropanol 50 g of lopinavir 11 gm of lopinavir 11 dissolve by heating the mixture on a hot plate to boiling point with magnetic stirring. Then the solution was cooled to room temperature and a precipitate formed. The resulting mixture was stirred at room temperature for a period just to keep the precipitate suspended. The precipitate was collected by Gals adsorption filtration by flipping del; 7 vo vv the half-crystalline lopinavir and dried in the air, yielding 9.9 g of suction filtration eI lopinavir form. Thermal analysis indicated gg of the type isopropanol solubility in isopropanol moles of Y per isopropanol 1 mole of isopropanol of the product to the presence of a volatile substance corresponding to

Cosh lopinavir 10010871 X-ray diffraction analysis of the powder showed that the product was M and infrared spectroscopy confirmed that the product is the soluble crystal form of the type ost of the Ly transformation of lopinavir +: (100108). The mid-infrared spectrum is shown 1!For samples in the solid state in Figure 4+ and the near-infrared spectrum is shown according to .04 Fourier transform for samples in the solid state in Figure 1 Example 17 type of lopinavir isopropanol Method for preparing a soluble crystal form in Isopropanol as determined by analysis Gos 71.76 in proportion isopropanol (containing thermogravitational lopinavir isopropanol) isopropanol ml of isopropanol Y,0 g of lopinavir 10010871 in 1 suspension diameter; 1 mm to consolidate glass beads in a glass vial containing four glass beads The mixing The vial was covered and the suspension was vigorously stirred at room temperature for a period of 1-months The solvent was left to evaporate slowly Then a Perri dish was placed and then transferred Suspended to a kilopascal petri dish at Tom and the sample was dried at Jon Petri in a vacuum oven; it was then warmed up to a day, producing the compound called the title. The product contained volatile matter YO for 0 m at a percentage of 71.1 as determined by thermogravimetric analysis. 0 Example A Method for the preparation of a soluble crystal form in isopropanol type 1 [of lopinavir] (containing isopropanol at 77 Gos as determined by scalar thermal analysis) A sample of the product of Example 1 was rinsed The cheptane was dried for two days in a rotary evaporator, and the ore was transferred to a petri dish and dried in a vacuum oven. Then warm to

Ya

kilopascals and at 12 m for a period of days, the compound called Von was produced, and the sample was dried at the address. The product contained volatile matter by 7 as determined by thermogravimetric analysis. The mid-infrared spectrum, according to the Fourbier transformation of samples in Weibten, shows the near-infrared spectrum according to the solid-state transformation.

Ne Fourier for samples in the solid state in Figure 4 ° Example II of type ethyl acetate Method for preparing a semi-soluble crystalline form in ethyl acetate lopinavir for lopinavir fq Example Crude lopinavir Method of preparation Lopinavir 01 Raw; Prepared in accordance with US Patent No. lopinavir dissolved lopinavir gm of (5)-pyroglutamic acid salt of Ao of approximately (YA Jd) 413

TFT) Roxy-0-[57-(1-tetrahydrrupyrimidonil-1-50)-7-amino 57 057((28,38,58)-2-amino-3-hydroxy-5- [28-Hexane Jd EE; Ethyl VIAL (corrected for solvent content) in acid salt g of ethyl acetate YYO solution in vacuum until oil is obtained. The ore was dissolved in water and then concentrated in a vacuum twice until oil was obtained. The concentrate was dissolved in cethyl acetate at 15 °C and filtered to remove any trace amounts (Lo ml Yo) ethyl acetate from insoluble solids; and concentrate in a vacuum until a foam is obtained. The foam © was dissolved and this solution was divided into four equal parts. ethyl acetate in 374 g ethyl acetate v4 example B

IT ethyl acetate method for preparation of a semi-soluble in ethyl acetate crystalline form of lopinavir = 1 part of a solution of lopinavir prepared in Example 4a in vacuo until oil is obtained; Then it was dissolved in 50 ml of pure ethanol. The solvent was removed in a vacuum. The ore was kept in a vacuum and heated to Ly ji a 1e—00 for an additional period of 0 minutes. The resulting foam was dissolved in AY ml of ethyl acetate at ambient temperature. and in Jil from © minutes of mixing; Solids appeared clearly. The resulting slurry was mixed for VT an hour and then diluted with AY ml of Ve.heptanes and after three hours; Solids were collected by filtration; washed with YY mL of a mixture of [EtOAc heptanes in a 1:1 volume/volume ratio; It was dried in a vacuum at 10 C for del VY, resulting in 14.4 g of the semi-soluble form of lopinavir in ethyl acetate of the type [. The mid-infrared spectrum, Gy, of the Fourier transform of samples in the solid state is shown in Figure 11. The spectrum of near infrared radiation 1 according to the Fourier transform of samples in the solid state is shown in Figure .016. 74.4 as determined by gravitational thermal analysis. Example C. An alternative method for preparing the semi-soluble in ethyl acetate type IT crystalline form of lopinavir Y. Crude lopinavir solvent; Prepared in accordance with U.S. Patent No. ody evry (Example (YA) from approximately 01 g of (5)-pyroglutamic acid salt of L(5857:0857)-7-amino-7-hydroxy-9-[57 - ( 1-tetrahydropyrimidonil (7))- *-methylbutanyl]amino-0;SE-phenylhexane (25,38,55)-2-amino-3-hydroxy-5-[25-] (I-tetrahydropyrimid-2-onyl)-3-methylbutanoyljamino-1,6-diphenylhexane (S)-pyroglutamic vo acid (corrected for solvent content) in 1118 g of ethyl acetate and then

; Concentrate in a vacuum until an oil is obtained. The ore was dissolved in 98.7 g of ethyl acetate at 7?um; Then it was concentrated in a vacuum until an oil was obtained. The ore was annealed in 90.0 g of ethyl acetate at 4 m. Moisture measurement using KF showed an ele of less than 70.09. The product solution was cooled to 14 °C and seeded with Yeo, 8 gm of Jal product. The solution was cooled to 75°C and mixed at that temperature for 1.75 hours. Then the resulting slurry was cooled to 10°C within 10 minutes; And mixed at a temperature ranging from 11-41 °C for 1.0 hours. The mad ill solids were collected, washed with 1.7 gm of cethyl acetate, and dried in a vacuum at a temperature ranging from < 7 °C for 116 hours, resulting in 17.7 gm of lopinavir 0. Semi-solubility in ethyl acetate from ALE sill Example 01 Method for preparing a crystalline form of solubility in ethyl acetate of type 1! For lopinavir VII (containing less than 1.6 moles of ethyl acetate per 1 mole of lopinavir: M1 as determined by thermogravitational analysis) Vo =—1 part of a solution of lopinavir prepared in Example 4a in a vacuum until oil is obtained; Then it was dissolved in 00 ml of pure ethanol. The solvent was removed in a vacuum. The ore was kept in a vacuum with heating (at a temperature ranging from approximately 0°C) for an additional period of 0 minutes. Initiating crystals from the pre-example product were added to the resulting foam. Then the foamed concentrate was dissolved in AY ml of 0 ethyl acetate at ambient temperature. and in less than 0 minutes of mixing; Solids appeared clearly. The resulting slurry was mixed for VT 1 hour; then diluted with AY ml of heptane 186018065 and after three hours; Solids were collected by filtration; It was washed with 71 ml of a mixture of 80/82/heptanes at a ratio of 1:1 v/v and dried in a vacuum at 20 m VY ad h, yielding 1.77 g of solubility in ethyl acetate. ethyl acetate Yo type 1! for lopinavir and ada bitumen (CID YYo)

1 The infrared spectrum VY of the Fourier transform of samples in the solid state is shown in the form Gig, and the near red VY according to the Fourbier transformation of the samples in the solid state in the produced figure contained a volatile substance with a percentage of 71.7 as determined by thermal analysis gravitational. B111 Ex. 1] of type ethyl acetate An alternative method for preparing a soluble crystal form in ethyl acetate | 0 per ? ethyl acetate of 0.8 mol ethyl acetate Jl (containing lopinavir mol of lopinavir: 10010871 as determined by thermo-technology) a solution of lopinavir 10010271 crude prepared according to a patent Invention =X) TY (SOSYSY) horn 17.0 g oY JEAN) 0414777 (USA No. phenylhexane JUN; 0-onema-0-iscordia-1-nima-phenoxyacetyl) Jha SE, with (28,38,58)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane g of 57-(1-tetrahydropyrimidonyl (7)) -7-methylbutanoic 0 in (EDAC/HOBT) by horning 2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoic acid in a vacuum until isopropyl acetate ml of isopropyl acetate was obtained YOO about and concentrated in a vacuum until ethyl acetate ml of ethyl acetate YO oil was obtained. The concentrate was dissolved in warm ve. And ethyl acetate divided 171 ml of ethyl acetate to obtain a foam. The foam was dissolved in solution into three portions of 0.6 g each.The solutions were cooled to ambient temperature where crystallization occurred rapidly thereafter.One of these portions was mixed at ambient temperature with ml acetate A overnight . Solids were collected by filtration; Washed with ethyl purification. then dried in a vacuum at 77°C for 560 hours; then dried for an additional period + amounted to ;; 1 hour in a vacuum at 0 Lm yielding 1.77 g of the soluble form in acetate 10M 108071:2 type 1 [for lopinavir ethyl acetate YYo]

Button 11 Jl Method for preparing a semi-soluble crystalline form in chloroform of type Il for lopinavir Dissolve 01 g of lopinavir in 710 ml of ~chloroform, then m Bring the solution to a boil on a hot plate with magnetic stir. and after reducing the volume of the solution to about ,/' the initial volume; About 10 mL of n-heptane was added dropwise until the solution began to become cloudy. Then more chloroform was added, in an amount of about 30 ml, and the boiling continued until the volume again reached “almost the original volume.” Then about 10 ml of chloroform was added, and the boiling continued until the volume reached All YL approximately the original volume.Then the mixture was slowly cooled to room temperature and allowed to partially evaporate.After slow evaporation I left two glass concentrates of the consistency of molasses and mixed this with about 0ml of chloroform and warmed on a hot plate.Then p-heptane was added drop by drop until a precipitate began to form.The precipitate was dissolved by heating the mixture again.The warm solution was transferred to a beaker flask and placed into a jar 1 containing about 10 mL of heptane and left to cool.After about one hour a thick solid precipitate was formed.Most of the precipitate was dissolved again by adding about 30 ml of chloroform to the contents of the beaker.After leaving this mixture to settle (ad) for about one hour A small amount of needle-shaped crystals formed.More heptane (about 0 Ja) was added to the jar containing the flask and the jar was covered and left to settle. after one day; The beaker contained a large number of crystals. The crystals were collected by vacuum filtration. The crystal mass was gently broken with a spatula and the crystals were washed with a mixture of heptane (isd chloroform) located in the jar outside the beaker where the crystals had grown. Thermal gravitational analysis of the product indicated the presence of a volatile substance corresponding to 1 mole of chloroform per ¥ mol of lopinavir (vo), and X-ray diffraction analysis of the powder showed that the product was crystalline, and spectroscopy (de SY) under

LY

Weiben -lopinavir red that the product is a soluble crystal form of type 11 for lopinavir Fourier transformation of samples in the solid state in the form lily mid-infrared spectrum Fourier transformation of samples in the state Wg Weiben infrared spectrum near red AY

Solid AA in Figure 11 Example HI of type ethyl acetate Method for preparing a crystalline form dissolved in ethyl acetate lopinavir for lopinavir JY) g of acetate 7.11 in lopinavir g of Lopinavir 7.17 ounces where the substances appeared Hida £0 at 1 lm. and cool the solution to 7 °C within ethyl acetate minutes; Then it was mixed for Fe through ATE solid for visualization at this temperature. The slurry was cooled to one minute and then mixed for an hour VY one hour. The slurry was then cooled to 10 m within a minute. VY mixed drop by drop with one 1.5 g of heptanes. The resulting solid was added by filtration; I washed a minute of gall. The resulting slurry was collected for a period of 910 cin jag mixed with heptanes heptane CLS jofethyl acetate 01 ml of a mixture of ethyl acetate using 1 gm of the compound NE an hour 01 volume / volume and dried in a vacuum At 67 m for a period of 1:1 in the ratio of the ve labeled with the title. X-ray diffraction analysis proved that the product is crystalline, and infrared spectroscopy confirmed that the product is a solute crystal form of type!! 1 of lopinavir for Fourier transformation of samples in Gig and mid-infrared spectrum 7 for transformation of Lig The solid state is shown in Fig. 19 and the near infrared spectrum is shown. The product contained a volatile substance with a ratio of LY Forbes to samples in the solid state in Fig. © as determined by thermal gravitational analysis. 7,”

tt 11 Example HI of the type ethyl acetate Method for preparing a soluble crystal form in ethyl acetate lopinavir Approximately 1,000,007 mg of lopinavir in about 100 ml of ethyl acetate 001 was dissolved and added to this solution Slowly and carefully about ¥ ml of heptane 1601286. After ethyl acetate M by lopinavir, crystals of lopinavir type 1 -liquid diffusion crytallization -liquid diffusion crytallization were grown.

VE JU

11] of the type ethyl acetate Method for preparing a soluble crystal form in ethyl acetate lopinavir for lopinavir ve 19 One part of the lopinavir 7 solution prepared in the example cig and heated to a temperature of ethyl acetate 1 g of acetate Ethyl 15,4 using, while the heptanes were kept on 1 g of heptane compounds VO and then diluted using VO (And the resulting solution was heated to 8 m for 2 Ve, the internal temperature so that it exceeds the night at dish and left to cool gradually to ambient temperature.After mixing 1 yo ml of 1 ambient temperature, the solids were collected by filtration, washed using volume/volume, and dried 1:1 to 80/ Heptane compounds 65 percent acetate A mixture of ethyl acetate An hour Vintage produced 71.59 g of the compound named VY in a vacuum at 10 m for a period

Yo Example lopinavir Method for preparing an insoluble crystalline form [!1] of lopinavir Tr. ml. Sufficient 1001 g of lopinavir 10010808 was added and placed in a beaker of capacity to dissolve approximately 790 ounces of lopinavir 100108013. Only some acetonitrile of the needle-shaped acetonitrile crystals remained insoluble. And the beaker was placed inside a jar containing a layer of depth: and covered. (DRIERITE) anhydrous calcium sulfate 1 cm of anhydrous calcium sulfate about 1 jar and the material was left undisturbed at ambient temperature. And after letting it settle throughout the vo

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go mL of supernatant 1 A large amount of white crystalline substance has precipitated. Applauded about oll: New Elsie acetonitrile from the beaker. A volume of 71 mL of the precipitating acetonitrile supernatant was added; Which is then gently broken using a spatula. The solid material was collected by filtration, and the acetonitrile solid was transferred from 1 ml of acetonitrile by sucking and rinsed using about 1 m to a Petri dish and dried in vacuum at ambient temperature, resulting in the soluble crystalline form of lopinavir type 1. X-ray diffraction analysis of powder 10 confirmed that the product is crystalline, and infrared spectroscopy confirmed that the product is a crystalline form of 10.09 type [11 for lopinavir: 0]. The product contained a volatile substance with less than the middle infrared spectrum according to Os as determined by thermogravimetric analysis. The infrared spectrum is shown 71. For the Fourbier transform of samples in the solid state in the figure. The diffraction pattern YY is shown for the Fourbier transformation of samples in the solid state in the figure close ly. 6 The NMR spectrum of YY X-ray powder of MHz is shown in Fig. 4 ?. A scheme of 0 for samples in the solid state at a frequency of YO is shown in the figure (DSC) thermal Differential Scanning Calorimeter 11 Example Vo lopinavir Method for preparing a non-solubility crystal form type 17 of lopinavir (1) crystallizing dish 5-155 amorphous in a dish lopinavir 1 g of lopinavir put 1 ml of acetonitrile 01 and placed this plate in a larger crystallization dish (B) containing approx. on a hot plate. He inverted a medium-sized crystallization plate (C) and placed fy y acetonitrile on top of plate (A) but still inside plate (B). A large crystallization plate (3) was inverted and placed on top of the plates © (a)» (b) and (c). The hot plate was warmed to about 75 °C, then the hot plate was turned off. 10 days at ambient temperature. After 10 The whole composition was then left to settle for a period of -acetonitrile all 0

A portion of the resulting crystalline product, 0 g, was mixed with 0.0 mL of acetonitrile and stirred for 1 hour. The mixture was filtered and the solid was left to dry in the air, resulting in a non-dissolving crystalline form of type IV for lopinavir Example 11 ° Method for preparing a non-dissolving crystalline form of type IV for lopinavir Dissolve 7594 g of lopinavir lopinavir in 9500 g of acetonitrile at a temperature ranging from 0?-7 °C. The cloudy solution was filtered through a nylon membrane with an eye diameter of 01.46 microns into a round bottom flask. Y liter capacity and the solution was seeded with a few crystals of Example 01 product and the flask was cycled at 7-010 rpm overnight without heating or vacuum using a rotary evaporator. A thick slurry of crystals resembling eplers was produced. The slurry was cooled in an ice bath for one hour and then filtered through a nitrogen-coated table-top Neutsche filter covered with a plastic film. The filter cake was washed using hil acetonitrile to dryness in nitrogen atmosphere for about 0 minutes. The filtrate was transferred to an aang crystallization plate over the weekend at a temperature ranging from −777.7-211.1 mmbar (0-71 inch Hg) with nitrogen bleed, resulting in 194.7 g. Of the insoluble crystal form type 17 of lopinavir: 8m10, the product was Gosh as determined by powder X-ray diffraction and classified as the non-soluble crystal form of 0 - type 17 of lopinavir +0 as determined by Fourier-transformed mid-infrared spectroscopy for samples in the solid state. The mid-infrared spectrum is shown according to the Forbier transform for samples in the solid state in figure Lvs, the near-infrared spectrum is shown according to the Forbier transformation for samples in the solid state in figure YY, and the X-ray diffraction pattern of a powder is shown in Figure 78. The nuclear resonance spectrum is shown The magnetic p' vs. s of solid-state samples at a frequency of 0 MHz is shown in Fig. 4?. The YYo plot is shown.)

A differential scanning calorimeter (DSC) calorimeter in Fig. “0.” The product contained less than 1/70 volatile matter as determined by thermogravimetric analysis. And when administering to treat HIV infection, it is preferable to give lopinavir in combination with ritonavir 0:4 du ritonavir (tlopinavir, ritonavir 0), and a preferred pharmacist composition for giving lopinavir 7a contains lopinavir: 108108“7: ritonavir 0:4 A ritonavir The following composition encapsulated in a soft flexible gelatin capsule Lopinavir 0 mg ritonavir 1 mg ritonavir Ve oleic acid acid 016:6 according to NF 1 mg Gi propylene glycol USP 1.1 mg polyoxyl 35 Castor Oil Yo according to NF 70.4 mg (Cremifor EL (registered trademark) (Cremephor EL® pure distilled water according to USP £7 mg and if a hydrated or soluble crystal form of lopinavir 1001021 is used in the composition; the amount of the hydrated or soluble crystal form of lopinavir is determined by taking the amount of water or other solvent present in the form The preferred composition, Gy, can be prepared for the following method.The following protocol is used to prepare 1,000 soft gelatin capsules.

L.A

Measurement Name Amount (mg/capsule) (g) Amount NF L Gi Nitrogen Adequate Nitrogen

OVA, NF for G5 coleic acid oleic acid OVA, a ritonavir ritonavir vey arc USP for Gi “propylene glycol” propylene glycol pulp 2 USP Purified water distilled according to gv 767 lopinavir lopinavir 1

Yo, NF According to coleic acid 0 7 NF L Gy “polyoxyl 35 Castor Oil Yo Polyoxyl Castor Oil Yh, ¢ 0 1 M NF L Gy (oleic acid) Then charge nitrogen and an appropriate mixing tank with nitrogen Clean mixing tank Mixing tank Heat mixing tank to oleic acid 5 g oleic acid 5”m ritonavir (without exceeding 17m) and start mixing. Then 3.9 gm of ritonavir propylene glycol was added with mixing, propylene glycol m oleic acid was added to the oleic acid and water to the mixing tank and mixing continued until the solution became clear, then 17.79 gm of oleic acid was added 01 of lopinavir 1000808 to the mixing tank and mixing continued.Then it was shipped to the tank and mixed until the solution became clear.1.4 gm of oleic acid was added according to the National Approximate Formula Book polyoxyl 35 castor oil YO castor oil 01 gm of polyoxyl acid was added to the mixing tank and mixing continued, followed by the addition of (NF) national formulary Ve until p AY and the solution was stored at a temperature ranging from -oleic acid to gm of the solution In each soft gelatin capsule and then dried ASS encapsulated. burden

AY soft gelatin capsules and stored at a temperature ranged from,

£4 as used in this statement; The term 'substantially pure L ja sa' when used with reference to the crystalline form of clopinavir refers to a 10:1 crystalline form of lopinavir having a purity greater than about 0. This indicates that the crystalline form of lopinavir does not contain More than about 0 of any particular Je AT compound M does not contain more than about 701 of any AT form of dlopinavir as the soluble, non-soluble and eluated amorphous crystalline forms. To a crystalline form of lopinavir that has a purity of more than about 1385730 means that the crystalline form of topinavir does not contain more than about 78% of any other compound, and in particular it does not contain more than about 75% of any al-form of lopinavir lopinavir as the amorphous, amorphous forms; Non-solubility and solubility. Even better, the term "consubstantial find" refers to a crystalline form of lopinavir 10008 having a purity greater than about JAY. This indicates that the crystalline JS of lopinavir contains no more than about 7 of any AT compound. In particular; Contains no more than about 7" of any AT form of clopinavir such as the soluble; By more than about 48. This means that the crystalline form of lopinavir: Maha does not contain more than about 77 of any GAT compound, and in particular it does not contain more than about 77 of any other form of clopinavir, such as the amorphous form Ye. soluble; other Js private; contains no more than about 71% of any AT form of lopinavir 10010877 as the amorphous forms; vo solubility Non-solubility and solubility.

o. The X-ray diffraction analysis of the powder samples was carried out in the following manner. Samples were prepared for analysis by X-ray diffraction by spreading the sample powder (ground into powder or using a mortar and pestle microscope slides using a mortar and pestle for limited quantity samples) as a thin layer on the sample holder glass microscope slides And the sample was evenly leveled with a microscope slide. Deploy the packages in one system of three “circular bulk holder SA” systems: a hot stage mount or a quartz zero background plate (similar composition to a quartz zero background plate). ). An X-ray diffraction analysis was conducted for the ¢Scintag powder (Scintag XDS 2000 0/0 diffractometer XDS 2000 6/0 using a 1 kW diffractometer equipped with a normal focus X-ray tube dail). Tube 01 with germanium solid state detector cooled with liquid nitrogen or coolant according to Peltier

Eat kV fo tliquid nitrogen or Peltier cooled germanium solid state detector (f0Y) X: 00-1 Zary range: SY) mA; source or ? Diffraction 80-6000 (Shimadzu, .0) Scan Rate:

Nal Equipped with scintillation detector fine focus X-ray tube “Shimadzu Vo mA; Luminance Source 71-50” kV and 0-40 Nal scintillation detector X-ray: 1”-2 N; Angular range: Navigator (07); Scan rate: ¥ deg/min) or kV and 50 scintillation detectors; Nicolet X-ray diffractometer 1-2

OY) mA; X-Ray Source: 00-601; Angular range: stern © (Scan rate: 7°/min). The relative humidity of the medium in the glass slide + (model heated platform relative humidity generator) can be adjusted using a relative humidity generator (VTI Corp. RH200) and the locations of the X-ray diffraction pattern peaks characteristic of the powders recorded pluralistic shapes and this variability was defined as 0.1 + in terms of angular locations (07) with an allowable variability of

YALE-YALY p5 Pharmacopeia authorized by the US Pharmacopoeia vo

01 (9951 m). The variance +1 ; is used when comparing two powder X-ray diffraction patterns. From a practical point of view; If you assign a diffraction pattern peak in one mode to a range of angular locations (8Y) representing the measured peak position + 1,1 and set a diffraction pattern peak in the other mode to a range of angular locations (07) representing the measured peak position + , 11 and if these two 0 peak positions overlap; In this case, the two vertices will have the same angular position (07). For example, if the peak of a diffraction pattern in one of the two patterns is assigned a peak position at 0.00, then for the purpose of comparison; The allowed variability would allow the peak to be assigned to a location in the range of 2.70 and if a comparison peak in the other diffraction pattern was assigned a peak position at <0 ,v0 then for the purpose of comparison the allowed variability would allow the peak to be assigned to a location in the range 0 ,75e - 0; Solid state in the following manner Use a Bruker AMX-400 meter with the following media: CP-MAS cross-polarized magic angle spining ¢ frequency 1 Spectrometer for BC 0011 MHz; pulse sequence 78-002187; contact time *.7 ms; spin rate 170060 Hz; recycle delay time 0.0 sec; number of scans q Near-infrared spectrum analysis performed According to the Forbes transformation in the following manner, the samples were analyzed in the form of pure undiluted powders and placed in a transparent glass vial with a mass of ov. 750 FT-IR spectrometer VO with the extension of a fiber optic probe to determine the diffuse reflection coefficient of the near infrared spectrum of the type Nicolet SabIR near infrared diffuse reflectance fiber optic probe accessory and using the following media: detector (PbS) beam splitter “CaF2 beamsplitter number of smears vo sample 06 resolution A cm”.

ov Forbes analysis of the mid-infrared spectrum was conducted for the samples in the following manner. The samples were analyzed in the form of pure and undiluted powders. And use a spectrometer

Vor Fourier Infrared Spectrum Analysis Nicollet Magna System

NIC-PLAN Nicolet Magna System 750 FT-IR spectrometer 'MCT-A liquid nitrogen cooled detector 4d Nicolet NIC-PLAN Microscope ° 14 mm. A VX mm VY of BaF2 dimensions was collected and the sample was placed on a disc holder for samples from. smear at resolution reached; cm, and the analysis was carried out using the differential scanning calorimeter of samples in the following manner. Use a ATA Cell Model 412920 calorimeter. Instruments Differential Scan Type A. t. any. Instruments with TA Thermal software. Instruments DSC cell TA Instruments DSC type 0 for data analysis. The analysis media were as follows: Thermal Solutions id ea) 7 LF version sus

Cw g aluminum sample weight: >-10 mg” and placed in a flat aluminum trough m/min in the presence of 1 tightly after making a small hole in the lid; The heating rate was: (at a rate of 0;-< © mL/min). nitrogen A cleaner stream of nitrogen from ambient temperature to All was carried out by heating lattice with m or © m/min. 1 m at a rate of 0. The foregoing is considered an illustration of the invention only and is not intended to identify the invention with the embodiments described. The obvious differences and changes to a person familiar with the technology are intended to be within the scope and nature of the invention set forth in the attached claims.

Claims (1)

oy protection elements --6 RT ~(S© «SY SY) of the compound crystalline hydrated form 4a crystalline form 1 -1 -tetracycline 1 - Y )- 5 dimethylphenoxyacetyl)amine_and<- 7- Hydroxy-7 EY Od(1)hydropyrimidonil-7-methylbutanyl)r (28,38,55)-2~(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(I) - phenylhexane ¢ -tetrahydropyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane ° -1 ¢Y)=Y—(So yi) 1 (of the compound crystalline form -" 1 lm) TY) mem Sy pa aT phenoxyacetyl)amino J Gia di Y EO md Hydropyrimidonil (7))-7-methylbutanyl) 1 (28,38,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(I-phylhexane) ¢ According to the element tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane ° in the infrared spectrum in the infrared spectrum peak has 1 protection 1 radiation spectrum The solid peak at a location within the range 1171-1187 cm, and the peak v in the solid state at a location within the infrared spectrum A. cm 1119-4 3 =(Se «SY » substantially pure compound F crystalline hydrated form Aas Gosh form -“ 1-1-(-7-acetyl)amino-7-hydroxyr(m) methyl seid SUT 7-(7 Y EO = dl(7-tetrahydropyrimidonyl)-7-methylbutanyl) r (28,38,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-( I-p-phylhexane-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane ° 1;- The crystalline form of the compound - (so SY SY) 7-7 7-binary : of saber-1(-"methylphenoxyacetycel)amine_o-?-hydroxy-*-(7 ET Od hydropyrimidonil (1))-7-methylbutanyl)r (25,38,55)-2 (2,6-dimethylphenoxyacetyljamino-3-hydroxy-5-(2-(I-phenylhexane ¢ l-abate) UG tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane 0 in case The infrared spectrum in the infrared spectrum peak protection 7 has a peak 1 of the solid Speak spectrum at a location within the range 1117-1567 cm' and a peak v in the solid state at a location within the infrared spectrum below Alhambra A Cam 1119-1 4 -1-(58 “sY SY) of the compound solvated crystalline form -o-1 -1 (-7(-* +-dimethylphenoxyacetyl)amine and - -hydroxy-7( EET Op dd butanoyl) die ((Y) tetrahydropyrimidonil r(28,38,55)-2+(2,6-dimethy phenoxyacetyl)amino-3-hydroxy-5- (2-(I-hexane Ji ¢) has a peak of tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,6-diphenylhexane 0 solid state at a location within the “infrared spectrum” Infrared spectrum 1 in infrared spectrum peak cm A peak 1177-1131 v peak and Taw peak 1103-1146 solid state at a location within range A in The solid state at a location within the infrared spectrum 4. 1171-4 01 SY) substantially pure of the compound solvated crystalline form solvated crystalline form - 1 9 +-dimethylphenoxyacetyl)amino-"-hydroxy-"Y)-Y—(s0 Ri Y EN Od Hydropyrimidonil (7))-7-methylbutanyl)-trans-1-7(r (28,38,55)-2-(2,6-dimethylphenoxyacety Damino-3-hydroxy-5- (2-(I-hexane Jd ¢) has a peak of tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,6-diphenylhexane ° 1 00 solid-state infrared spectrum at a location within the range 7 1177-1151 cm a; peak in the infrared spectrum in A solid state at a location within the range 1167-1646 cm | And a peak in the infrared spectrum 9 in the solid state at a location within the range 1171-4 01 cm '. -1-1 crystalline form of the compound (ET 7(-7-)55 (g¥ SY) (Ss, Y acetyl) =u) Yom Saar r hydropyrimidonil (7 ))-7-methylbutanoyl) IT Od phenyl (28,38,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(1- Ob <a ¢ tetrahydropyrimid-2-ony1)-3-methylbutanoyl)amino-1 ,6-diphenylhexane ° has a peak in the infrared spectrum of the solid state at a location within the range 18-1177 v cm '. 1 hydropyrimidonil (1))-methylbutatoyl)amino-0” did EN ¢ Hc__san (28,38,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-( 2-(1- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,6-diphenylhexane° has a peak in the infrared spectrum of 1 in the solid state at a location within the range 1177-0 7 cm A and a peak in the infrared spectrum in A solid state at a location within the range 11497-11179 cm '. 1 4- Intrinsically pure crystalline form of compound (V) in “SY 58)- dissolved 1- Y-dimethylphenoxyacetyl (bo) TY) mem Spare Ch phenyl SE Vd butanoyl) Jie T= ((Y) hydropyrimidonil 1 (28,38,58)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-( I-Xan 1 at peak has a peak of tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,6-diphenylhexane ° in the solid state at a location within the infrared spectrum Alhambra .' 1117-08 v -1-(50 "s¥ SY) substantially pure from the compound crystalline form - 1 VY) mom amino-?-hydroxy-(Jd methyl) SET (Y) Y anth-1 = sal butanyl) Jie ((Y) tetrahydropyrimidonil r (28,38,58)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy- 5-(2-(I-phenylhexane § at peak has a peak of tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,6-diphenylhexane ° in the solid state at a location within the infrared range spectrum Infrared spectrum 1 in infrared spectrum peak 11177-00 77 cm '1157-1179 solid state at a location within the range A ~(So SY 7) solvated crystalline form 1-1-1(-7(-0-methylphenoxyacetyl)amino-7-hydroxy-ET "-(7; Y ET; 0-Unbema(1)tetrahydropyrimidonyl-7-methylbutatoyl) 1(28,35,55)-2+(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-S5-(2-(1-) Hexane J vid $ has a peak of tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1 ,0-diphenylhexane ° solid state at a location within the infrared spectrum 1 . cm 1TIY 1100 Range 58 (v -) SY isY) of the compound solvated crystalline form 1-1 (TN) ome sd (TN) ome sd oleanth-1 - ov 1 tetrahydropyrimidonil (7))-7-methylbutanyl) eT = pl J vi ¢ hexane (28,35,55)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-3- (2-(l- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane° has a peak in the infrared spectrum of 1 in the solid state at a location within 1177-1755 5a cm A and a peak Speak infrared spectrum A in the solid state at a location within the range J an VTEVAIYT 0-1 solvated crystalline form Goa sa From the compound SY) ET »1(-7-)55 SY Y methylphenoxyacetyl)amino-7-hydroxy-*- 1(7-(1-tetrahydropyrimidonyl (7))-7-methylbutanyl ) Aminsu-0; ET J vid ¢ hexane (28,3S,58)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(1-tetrahydropyrimid-2-onyl)- 3-methylbutanoyl)amino-1,6-diphenylhexane ° has a peak of 1 in the infrared spectrum in the solid state at a location within the v range 1167-1585 cm'. 1 0 A substantially pure solvated crystalline form of the compound SY AEST 7(-7-)50 SY Y methylphenoxyacetyl)amino-?-hydroxy-*-r (7-) (1-tetrahydropyrimidonyl(7))-7-methylbutanoyl)amino-1;+-dimethylphenyl-J— 138 g hexane (25,38,55)-2-(2,6-dimethylphenoxyacetyl)amino -3-hydroxy-5-(2-(I- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane° has a peak in 1 of the infrared spectrum. In the solid state at location 7 within the range 017-1635900 cm" and a peak in the infrared spectrum A, the solid state at a location within the range 1147-1179 cm '.