BG107165A - Crystalline pahrmaceutical forms - Google Patents

Abstract

The invention relates to new crystalline forms of lopinavir with peaks in the solid phase infrared spectrum in the interval 1652-1666 cm-1 and 1606-1615 cm-1, and to methods for their preparation. The crystalline forms are used for the purification or isolation of lopinavir or for the production of pharmaceutical preparations. 23 claims, 31 figures

Description

This invention relates to novel crystalline forms of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- (2- (1tetrahydropyrimid-2-one) -3-methylbutanoyl) amino -1,6diphenylhexane (also known as lopinavir) and methods for their preparation. The new crystalline forms of the invention may be used to purify or isolate lopinavir or to prepare pharmaceutical preparations for the administration of lopinavir.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) protease inhibitors were approved several years ago for use in the treatment of HIV infections. A particularly effective and recently approved HIV proease inhibitor is (2S, 3S, 5S) -2 (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- (2- (1-tetrahydropyrimid-2-one) -3-methylbutanoyl) amino-1,6-diphenylhexane (also known as lopinavir).

Lopinavir is known to have the ability to inhibit HIV protease and inhibit HIV infection. Lopinavir is particularly effective for inhibiting HIV protease and inhibiting HIV infection when co-administered with ritonavir. Lopinavir in combination with ritonavir is also particularly effective in inhibiting HIV infection when used together with one or more reverse transcriptase inhibitors and / or one or more other protease inhibitors.

Lopinavir and methods for its preparation are described in U.S. Patent No. 5,914,332 of June 22, 1999, which is incorporated herein by reference. This patent also describes methods for the preparation of amorphous lopinavir.

Pharmaceutical preparations containing lopinavir or its pharmaceutically acceptable salts are described in U.S. Patent No. 5,914,332 of June 22, 1999; U.S. Patent Application No. 08 / 966,495, filed Nov. 7, 1997; U.S. Provisional Patent Application No. 60 / 177,020, filed Jan. 19, 2000, and U.S. Patent Application No. 09 / 487,739, filed Jan. 19, 2000, all of which are incorporated herein by reference.

It has been unexpectedly discovered that lopinavir can be prepared and isolated individually by any one of a plurality of crystalline forms.

»

Short description of the figures

FIG. 1 is the X-ray powder diffraction profile of a Type I hydrated crystalline form of lopinavir comprising about 0.5 molecules of water per molecule of lopinavir.

• «· · · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

FIG. 2 is a 100 MHz solid-phase ¹³ C spectrum of the Type I hydrated crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir.

FIG. 3 is the FT near infrared solid phase spectrum of a Type I hydrated crystalline form of lopinavir, comprising about 0.5 molecule mode for a lopinavir molecule.

FIG. 4 is the FT average type I infrared solid phase spectrum of a hydrated crystalline form of lopinavir, comprising about 0.5 molecules of mode for a lopinavir molecule.

FIG. 5 is a powder X-ray diffraction pattern of Type I, a more hydrated crystalline form of lopinavir.

FIG. 6 is the 100 MHz solid phase spectrum of the Type I nuclear resonance type I more hydrated crystalline form of lopinavir.

FIG. 7 is the FT near Type I infrared solid phase spectrum of the more hydrated crystalline form of lopinavir.

FIG. 8 is the FT average Type I infrared solid phase spectrum of the more hydrated crystalline form of lopinavir.

FIG. 9 is the FT average type II infrared solid phase spectrum of isopropanol hemisolvated crystalline form of lopinavir.

FIG. 10 is the FT average type II infrared solid phase spectrum of an isopropanol solvated crystalline form of lopinavir having about 2% solvent in thermal gravimetry.

FIG. 11 is the FT mean type II infrared solid phase ethyl acetate hemisolvated crystalline form of lopinavir.

FIG. 12 is the FT average solid phase infrared spectrum of

Type II ethyl acetate solvated crystalline form of lopinavir having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir by thermal gravimetry.

FIG. 13 is the FT mean solid-phase spectrum of the Type P chloroform hemisolvated crystalline form of lopinavir.

FIG. 14 is the FT near infrared solid phase spectrum of type II isopropanol hemisolvated crystalline form of lopinavir.

FIG. 15 is the FT near infrared solid phase spectrum of type II isopropanol solvated crystalline form of lopinavir having about 2% solvent in thermal gravimetry.

FIG. 16 is the FT near infrared solid phase spectrum of type II ethyl acetate hemisolvated crystalline form of lopinavir.

FIG. 17 is the FT near infrared solid phase spectrum of type II ethyl acetate solvated crystalline form of lopinavir having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir by thermal gravimetry.

FIG. 18 is the FT near-infrared solid phase spectrum of type II chloroform hemisolvated crystalline form of lopinavir.

FIG. 19 is the FT mid-infrared solid phase spectrum of type III ethyl acetate solvated crystalline form of lopinavir.

FIG. 20 is the FT near infrared solid phase spectrum of type III ethyl acetate solvated crystalline form of lopinavir.

FIG. 21 is the FT average Type III infrared solid phase spectrum of a desolvated crystalline form of lopinavir.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

1 · · · · · · · · · · · · · · · · · ·

FIG. 22 is the FT near infrared solid phase spectrum of

Type III desolvated crystalline form of lopinavir.

FIG. 23 is the powder X-ray diffraction profile of type III desolvated crystalline form of lopinavir.

. FIG. 24 is the 100 MHz solid phase ¹³ C spectrum of type III desolvated crystalline form of lopinavir.

FIG. 25 is a differential scanning colorimetric (DSC) thermogram of a Type III desolvated crystalline form of lopinavir.

FIG. 26 is the FT average solid phase infrared spectrum of

Type IV non-solvated crystalline form of lopinavir.

FIG. 27 is the FT near infrared solid phase spectrum of

Type IV non-solvated crystalline form of lopinavir.

FIG. 28 is the powder X-ray diffraction profile of Type IV non-solvated crystalline form of lopinavir.

FIG. 29 is the 100 MHz solid phase spectrum of ¹³ C Type IV non-solvated crystalline form of lopinavir.

FIG. 30 is a differential scanning colorimetric (DSC) thermogram of a Type IV non-solvated crystalline form of lopinavir.

FIG. 31 is the powder X-ray diffraction profile of type III solvated (ethyl acetate) crystalline form of lopinavir.

'W · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · * · · · · · · · · · · · · · · · · · ·

Description of the invention

According to the present invention, there are new crystalline forms of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- (2- (1 tetrahydropyrimid-2-one) -3-methylbutanoyl) amino -1,6diphenylhexane (lopinavir).

According to one method of the present invention there are hydrated crystalline forms of lopinavir. To identify them, hydrated crystalline forms referred to as Type I. Type I hydrated crystalline forms of lopinavir include from about 0.5 molecules of water per molecule of lopinavir to about 2 molecules of water per molecule of lopinavir.

Type I hydrated crystalline forms of lopinavir are used in the purification or isolation of lopinavir during the final steps of the lopinavir production process and in the preparation of pharmaceutical preparations for the administration of lopinavir.

The type I hydrated crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, is hygroscopic. Therefore, while not stored at conditions of about 0% relative humidity, the Type I hydrated crystalline form of lopinavir contains more than 0.5 molecules of water per molecule of lopinavir. If a hydrated crystalline form of lopinavir of Type I is dehydrated to less than 0.5 molecules of water per molecule of lopinavir, amorphous lopinavir is obtained.

Because Type I hydrated crystalline forms of lopinavir, comprising 0.5 molecules of water for the lopinavir molecule and about 2 molecules of water for the lopinavir molecule, represent, respectively, the lower and upper bounds of the solvation water observed for the crystalline hydrated forms of lopinavir Type I, the water content the crystal shape can vary in? * '·

Whose range within this range depends on the temperature and water content of the crystalline environment. The term "Type I more hydrated crystalline form" will be used herein to refer to Type I hydrated crystalline forms of lopinavir containing from more than 0.5 molecules of water per molecule of lopinavir to about 2 molecules of water per molecule of lopinavir. Specifically, Type I, the more hydrated crystalline form of lopinavir contains from about 0.75 to about 1.9 molecules of water per molecule of lopinavir. In particular, the Type I more hydrated crystalline form of lopinavir contains from about 1.0 to about 1.8 molecules of water per molecule of lopinavir.

In a preferred method, Type I hydrated crystalline forms of lopinavir are substantially pure as compared to other forms of lopinavir, including amorphous, solvated forms, unsolvated and desolvated forms.

It has been found that the FT mid-infrared solid phase spectrum is a means of characterizing Type I hydrated crystalline forms of lopinavir and distinguishing hydrated crystal forms from other crystalline forms of lopinavir.

Type I hydrated crystalline forms of lopinavir (including virtually pure Type I hydrated crystalline forms of lopinavir) have the characteristic FT mid-infrared solid phase bands shown in Table 1. Table 1 shows the interval of peak positions for each of the 17 characteristic mid-infrared mid-infrared bands. solid phase spectrum of type I hydrated crystalline forms of lopinavir. This means that any Type I hydrated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in the Table 1.

Most typical of Type I hydrated crystalline lopinavir forms (including virtually pure Type I hydrated crystalline lopinavir forms) are FT positions of mid-infrared solid phase bands for amide bonded carbonyl elongation. These bands are located in the range 1652-1666 cm < -1 & gt ^; and 1606-1615 cm < -1 ^> for Type I hydrated crystalline forms of lopinavir. Any Type I hydrated crystalline form lopinavir (including substantially pure Type I hydrated crystalline forms lopinavir) will have a peak at a position in the range of 1652-1666 cm ^'1 and peak position in the range 1606-1615 cm' ^1.

Type I hydrated crystalline forms of lopinavir (including virtually pure Type I hydrated crystalline forms of lopinavir) are further characterized by an infrared solid phase peak at a position within each of the intervals 778-783 cm ⁴ , 765-769 cm ⁴ , 755-759 cm ⁴ and 738-742 cm ⁴ .

• · · · · · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 9999

Table 1

Solid-state FT peak position intervals of mid-infrared bands for Type I hydrated crystalline lopinavir

Minimum cm ' ¹ Maximum cm ' ¹ Intensity * 3495 3505 Sl / absent 3371 3386 C / SS 3281 3299 SS 3058 3064 Sl 3024 3031 Sl 2958 2967 In 2926 2938 Sl 2868 2875 Sl 1652 1666 MS 1606 1615 C / SS 1524 1532 p 1450 1456 SS 1404 1410 Cl / MSl 1304 1311 SS 1187 1197 SS 1089 1094 In 1048 1056 Sl

* Cl = weak; B = moderate; CC = medium strong; C = strong; MS = very strong ·· ·· ··· ·· ·· ····

Type I crystalline form of lopinavir comprising about 0.5 molecules of water per molecule of lopinavir has a powder X-ray diffraction profile, which is presented in FIG. 1. The type I crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, has a solid-phase ¹³ C nuclear magnetic resonance spectrum, FT near infrared spectrum and FT medium infrared spectrum, which are presented in Figs. 2, 3 and 4. The sample from which the infrared and nuclear magnetic resonance spectra are obtained may contain slightly more than 0.5 molecules of water per molecule of lopinavir due to the hygroscopicity of the crystalline form when the hydration level is about 0.5 molecules water for the lopinavir molecule.

Positions of two-theta angles of characteristic peaks in the X-ray powder diffraction pattern of Type I hydrated crystalline lopinavir containing about 0.5 molecules of water for the lopinavir molecule (including virtually pure Type I hydrated crystalline forms of lopinavir, including 0.5 molecules of water for the lopinavir molecule) as shown in FIG. 1, ca: 7.25 ° ± 0.1 °, 8.53 ° + 0.1 °, 10.46 ° ± 0.1 °, 11.05 ° ± 0.1 °, 11.71 ° ± 0.1 °, 14.76 ° ± 0.1 °,

15.30 ° + 0.1 °, 16.67 ° + 0.1 °, 17.32 ° ± 0.1 °, 19.10 ° ± 0.1 °, 19.57 ° ± 0.1 °, 21.24 ° ± 0.1 °, 21.84 ° ± 0.1 ° and 22.46 ° ± 0.1 °.

Type I hydrated crystalline forms of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, can be obtained from a solution or suspension in water, or from solutions in mixtures of water and water-soluble organic solvents. Examples of water-soluble organic solvents are C1-C4 alcohols such as methanol, ethanol and the like;

acetonitrile; and similar. The amount of water in mixtures of water and water-soluble organic solvents can range from about 10% by volume to about 90% by volume (in particular from about 40% to about 60% by volume). In a preferred Type I method, the more hydrated crystalline form of lopinavir can be obtained by crystallizing a hydrated form of lopinavir from a warm solution in a mixture of water and ethanol, followed by prolonged exposure in an environment with increased relative humidity.

In addition, a Type I more hydrated crystalline form of lopinavir can be obtained by hydrating a Type I hemihydrated crystalline form of lopinavir at elevated relative humidity (e.g., at a relative humidity of about 20% or more).

Type I, the more hydrated crystalline form of lopinavir has a powder X-ray diffraction profile, solid-phase ¹³ C nuclear resonance, solid-phase FT near-infrared, and solid-phase FT mid-infrared spectra, respectively. 5,6,7 and 8.

Positions of the two-theta angles of characteristic peaks in the X-ray powder diffraction profile of Type I more hydrated crystalline lopinavir (including actually pure Type I more hydrated crystalline lopinavir), as shown in FIG. . 5, ca: 3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.57 ° + 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° ± 0.1 ° and 22.74 ° ± 0.1 °.

In particular, Type I more hydrated crystalline lopinavir (including the virtually pure Type I more hydrated crystalline lopinavir) is characterized by peaks in the powder X-ray diffraction pattern having positions at two-theta angles, shown in FIG. 5: 3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.06 ° ± 0.1 °, 15.57 ° ± 0.1 °, 16.49 ° ± 0.1 °, 17.51 ° ± 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° + 0.1 °, 21.73 ° ± 0.1 ° and 22.74 ° ± 0.1 °.

The individual parameters for X-ray crystallography and the experimental details for Type I more hydrated crystalline form of lopinavir are as follows:

Separate parameters for X-ray crystallography and experimental details for Type I more hydrated crystalline lopinavir

Experimental details Crystal data

Crystal System Grid parameters

Space group

With value

Deale

Monoclinic a = 46.922 (2) A b = 13.9945 (4) A c = 11.7231 (4) A β = 105.605 (1) ° V = 7414.2 (4) A ³ C2 (# 5)

1.19 g / cm ³

Intensity measurements

Bruker SMART diffractometer ·· ····

Radiation

Temperature

20x

Correction

Number of Reflections Measured • · · ······

The mo Κα (λ = 0.7107 A) is stable

46.6 °

Lorentz - polarization

Total: 27795

Dissolution of the structure and purification

Number of observations (Ι> 3.0 σ (I)) 5368

Number of variables 932

Reflections / attitude of

W * · 'parameters

5.76

Residues: R; Rw

0.107; 0.128

In two other methods of the present invention crystalline forms of lopinavir are solvated. Based on a single determination of X-ray crystal structure, the first method of solvated crystalline forms of lopinavir comprises a crystal structure in which clusters of lopinavir molecules bind to each other through hydrogen bonds and are arranged along the short crystallographic axis. Solvent molecules do not play a role in the hydrogen bond, but simply fill pockets that exist between the clusters of lopinavir molecules. For identification purposes, the solvated crystalline lopinavir forms of this method are designated Type II.

Based on the single determination of X-ray crystal structure, the second method of solvated crystalline forms of lopinavir involves a crystal structure in which the lopinavir molecules are bonded to hydrogen bonded sheets, the sheets with ····· · ·· · · * • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hydrogen-coupled lopinavir molecules are twisted, forming channels that are filled with variable amounts of solvent molecules. Solvent molecules do not play a role in the hydrogen bond in the second method of solvated crystalline lopinavir. For the purpose of identification, solvated crystalline forms of lopinavir by this method are referred to as Type III.

Type II

Type II solvated crystalline forms of lopinavir are used to prepare or isolate lopinavir during the final steps of the lopinavir production method.

Type II solvated crystalline forms of lopinavir are particularly useful for the preparation of crystalline lopinavir, which is free of, or has greatly reduced amounts of, the various impurities that are obtained by the method of preparation of lopinavir.

Type P solvated crystalline forms of lopinavir are typical hemisolvates. In other words, for each asymmetric unit of the crystal there are two molecules of lopinavir and one molecule of solvent. Low levels of solvation are also possible. Type II solvated crystalline forms of lopinavir can be partially desolvated by heating under vacuum. However, if more than about 75% of the maximum permissible solvent is removed (the maximum permissible is hemisolvated), amorphous lopinavir is obtained. Therefore, type II solvated crystalline forms of lopinavir range from about 0.125 solvent molecules per molecule lopinavir to about 0.5 solvent molecules per molecule lopinavir.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ · ·· f ·· · »* ··· ♦♦

Type II solvated crystalline forms of lopinavir comprise relatively small polar organic solvents. Examples of such relatively small polar organic solvents are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-amyl alcohol, isoamyl alcohol, t-pentanol, ethyl acetate, acetone, tetrahydrofuran, methane chloride, propylene glycol, methyl ethyl ketone, dimethyl sulfoxide and the like.

In the preferred Type II method, the solvated crystalline forms of lopinavir are substantially pure compared to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, non-solvated and desolvated forms.

The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing Type II solvated crystalline forms of lopinavir and differentiating Type II solvated crystal forms from other crystalline forms of lopinavir.

Type II solvated crystalline forms of lopinavir (including virtually pure Type II solvated crystalline ** forms of lopinavir) have the characteristic solid phase FT mid-infrared bands shown in Table 2. Table 2 shows the interval of peak positions for each of the 18 characteristic mid-infrared solid-phase bands. FT mean infrared spectrum of type II solvated crystalline forms of lopinavir. This means that any type II solvated crystalline form of lopinavir will have a position peak within the interval (minimum to maximum) for each of the peaks shown in Table 2.

* · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Most typical of Type II solvated crystalline lopinavir forms (including virtually pure Type II solvated crystalline lopinavir forms) are the positions of solid phase FT mid-infrared bands for amide bonded carbonyl elongation. These bands are located in the range 1661-1673 cm < -1 > 1645-1653 cm < -1 ^> and 1619-1629 cm < ¹ & gt ^; for Type II solvated crystalline forms of lopinavir. Any type II solvated crystalline form of lopinavir (including virtually pure Type II solvated crystalline forms of lopinavir) will have a peak at a position in the range 1661-1673 cm ' ¹ , a peak at a position in the range 1645-1653 cm' ¹ and a peak at a position at interval 1619-1629 cm ' ¹ .

Type II solvated crystalline forms lopinavir (including substantially pure Type II solvated crystalline forms lopinavir) is further characterized by an infrared solid-phase peak position within each of the intervals 776781 cm ^'1, 767-771 cm' ^1, 747-758 cm ⁴ and 742-746 cm ⁴ .

• 9 ··· • »• · · • * • ·>

·· 9 *

• • 9 « 9 • · 4 • · · 9 • 9 9 · • · · • · • • • · » • · 9 • 9 · · · • · ····

Table 2

Peak position intervals for solid-phase FT mid-infrared bands for Type II solvated crystalline lopinavir

Minimum cm ' ¹

Maximum cm ' ¹

Intensity * *

3391 3415 In 3324 3340 SS 3057 3063 Sl 3023 3029 Sl 2961 2970 In 2913 2938 Sl 2866 2879 Sl 1661 1673 P 1645 1653 P 1619 1629 MS 1540 1548 SS 1514 1522 p 1450 1456 SS 1418 1426 In 1302 1309 In 1181 1193 SS 1089 1095 In 1045 1056 Sl Cl = weak; B = moderate; SS = average strong; (

= strong;

MS = very strong ·· ··· ♦ e · ··· • · · ·· · V ·· • «· ·· • ♦ · · ·· λ ·· ·· ······

The solid-phase FT medium infrared spectra of the Type II solvated crystalline forms of lopinavir (isopropanol, ethyl acetate and chloroform) are given in Figs. 9, 10, 11, 12 and 13. The solid phase FT near-infrared spectra of the Type II solvated crystalline forms of lopinavir (isopropanol, ethyl acetate and chloroform) are given in Figs. 14, 15, 16, 17 and 18.

Type II solvated crystalline forms of lopinavir can be prepared by suspending excess solid lopinavir in the solvent and allowing the suspension to equilibrate over time. The Type II solvated crystalline form of lopinavir was then isolated by filtration.

Type II solvated crystalline forms of lopinavir can also be obtained by slow evaporation of the solvent from a solution of lopinavir. The Type II solvated crystalline form of lopinavir was then isolated by filtration.

Type II solvated crystalline forms of lopinavir can also be prepared by slowly adding an anti-solvent to a heated solution of lopinavir in the solvent, thus causing crystallization. The Type II solvated crystalline form of lopinavir was then isolated by filtration.

The individual X-ray crystallographic parameters and the experimental details for Type II ethyl acetate hemisolvated crystalline lopinavir and Type P chloroform hemisolvated crystalline lopinavir are as follows:

Separate X-ray crystallographic parameters and experimental details for type II etmlacetia hemisolvated crystalline form lopinavir

Experimental details Crystal data

Crystal system

Grid parameters

Space group

With value

Deale

Monoclinic a = 11.3456 (1) A b = 33.9490 (2) A c = 9.8641 (2) A β = 89.930 (1) ° V = 3799.37 (7) A ³ P21 (# 4)

1.18 g / cm ³

Intensity measurements

Diffractometer

Radiation

Temperature

20 things

Correction

Number of reflections measured

Bruker SMART

Mo Κα (λ = 0.7107 A) is stable

46.7 °

Lorentz - polarization

Total: 14824

Unique: 5211

Dissolution of the structure and purification

Observation count (1> 3.0 σ (I)) 4411

Number of variables 882

Reflections / ratio of parameters

5.0

Residues: R; Rw

0.104; 0.099 • «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Separate X-ray crystallographic parameters and experimental details for Type II chloroform hemisolvaLopinavir crystal crystal form

Experimental details

Crystal data

Crystal System Grid parameters

Space group

With value

Deale

Orthorhombic a = 9.7703 (51) A b = 33.410 (2) A c = 11.4874 (6) A V = 3749.8 (3) A ³ P21212 (# 18) 4

1.22 g / cm ³

Intensity measurements

Diffractometer

Radiation

Temperature

20 things

Correction

Number of reflections measured

Bruker SMART

Mo Κα (λ = 0.7107 A) is stable

46.6 °

Lorentz - polarization

Total: 14960

Unique: 4359

Dissolution of the structure and purification

Number of observations (Ι> 3.0 σ (I)) 4234

Number of variables 438

Reflections / ratio of parameters 9.67

Residues: R; Rw 0.094; 0.104

Type III

Type III solvated crystalline forms of lopinavir are useful in purifying and isolating lopinavir in the last steps of the lopinavir production process.

Type III solvated crystalline forms of lopinavir are particularly useful for the preparation of crystalline lopinavir, which is free-form or has greatly reduced amounts of various impurities resulting from the method of preparation of lopinavir.

Type III solvated crystalline forms of lopinavir are thermodynamically stable crystalline forms isolated from solvents, which generally include hydrophobic organic solvents or solvents that are too large to match the crystal lattice of Type II solvated crystalline forms of lopinavir. Type III solvated crystalline forms of lopinavir include solvents including n-hexanol, pctanol, 3-ethyl-3-pentanol, polyethylene glycol, ethyl acetate, isopropyl acetate, n-butyl acetate, glyceryl triacetate, acetone, methyl 2-isobutyl ketone 4-dimethylpentanone, alpha-tetralone, methyl t-butyl ether, 2,2,4,4-tetramethyltetrahydrofuran, isosorbide dimethyl ether, toluene, tetralin, nitrobenzene, p-xylene, sulfolane, hexane, heptane, decalin, oleic acid .

In a preferred method, type III solvated crystals of lopinavir form are virtually pure compared to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, unsolvated and dissolved forms.

The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing Type III solvated forms of lopinavir from other crystalline forms of lopinavir.

Type III solvated crystalline forms of lopinavir (including virtually pure Type III solvated crystals of lopinavir) have the characteristic solid phase FT mid-infrared spectrum shown in Table 3. Table 3 shows the range of peak positions for each of the 16 characteristic mid-infrared bands. of solid-phase FT mid-infrared spectrum of type III solvated crystalline forms of lopinavir. This means that each Type III solvated crystalline form of lopinavir will have a peak in the range (minimum to maximum) position for each of the peaks shown in Table 3.

The most characteristic type III solvated crystalline form of lopinavir (including virtually pure Type III solvated crystalline form of lopinavir) are the positions of solid-weight FT mid-infrared bands for amide coupled carbonyl elongation. The band is localized in the range 1655 - 1662 cm < -1 ^> for Type III solvated crystalline forms of lopinavir. Often, a second strip is located in the range 1636-1647 cm ¹ for Type III solvated crystalline forms of lopinavir. However, in some cases, the second strip (in the range 1636-1647 cm < -1 ^> ) appears as a shoulder of the first strip or is not sufficiently separated from the first strip to be distinguished as a second strip. Each Type III solvated crystalline form of lopinavir (including virtually pure Type III solvated crystalline form of lopinavir) will have a peak in position in the range 1655-1662 cm ' ¹ and may also have a peak in position in the range 1636 1647 cm' ¹ .

Type III solvated crystalline forms of lopinavir (including fastically pure Type III solvated crystalline forms of lopinavir) are further characterized by solid-phase infrared peak at position in the ranges 772-776 cm '\ 766-770 cm' ¹ and 743-747 cm ' ¹ .

The positions of the two theta angles of characteristic peaks in the X-ray powder diffraction profile of a Type III solvilane (ethyl acetate) crystalline form of lopinavir (including virtually pure Type III solvate (ethyl acetate) crystalline form of lopinavir) FIG. 31 are: 4-85 ° ± 0.1 °, 6.52 ° ± 0.1 °, 7.32 ⁰ ± 0.1 °, 12.82 ° ± 0.1 °, 12.96 ° ± 0.1 °, 16.49 ° ± 0.1 °, and 19.31 ° ± 0.1 °.

Table 3

Peak position intervals for solid phase FT mid-infrared bands for Type III solvated and desolvated crystalline forms of lopinavir

Minimum cm ⁴ Maximum cm ⁴ Intensity * 3394 3405 P 3278 3302 SS 3061 3071 Sl 3024 3033 Sl 2954 2965 In 2924 2936 Sl 2853 2872 Sl 1655 1662 MS 1636 1647 p 1517 1525 p 1501 1513 SS 1450 1455 SS 1300 1309 SS 1193 1200 SS 1090 1098 Sl 1051 1057 In

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· ·· ··· ·· ·· ···· * Sl = weak; B = moderate; CC = medium strong; C = strong; MS = very strong

The solid phase FT medium infrared spectrum of type III ethyl acetate solvated crystalline form of lopinavir is shown in FIG. 19. The solid phase FT infrared spectrum in the near region of Type III ethyl acetate solvated crystalline form of lopinavir is shown in FIG. 20.

Type III solvated crystalline forms of lopinavir can be prepared by suspending excess solid lopinavir in a solvent and allowing the suspension to equilibrate for some time. The Type III solvated crystalline form of lopinavir was then isolated by filtration.

The type III solvated crystalline form of lopinavir can also be obtained by cooling a saturated solution of lopinavir

Type III solvated crystalline forms of lopinavir can also be prepared by allowing the solvent to slowly evaporate from the lopinavir solution. The Type III V solvated crystalline forms of lopinavir were then isolated by filtration.

Type III solvated crystalline forms of lopinavir can also be prepared by slowly adding an anti-solvent to the heated solution of lopinavir in a solvent and thus induce crystallization. The type III solvated crystalline forms of lopinavir are then isolated by filtration.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Separate X-ray crystallographic parameters and experimental details for Type III ethyl acetate hemisolvated crystalline form lopinavir

Experimental details

Crystal data

Crystal system

Grid parameters

Space group

With value

Deale

Orthorhombic a = 23.961 (9) A b = 27.58 (1) A c = 11.967 (4) A V = 7907 (5) A ³ P2221 (# 20)

1.22 g / cm ³

Intensity measurements Diffractometer

Radiation

Temperature

20x

Correction

Number of reflections measured

RigakuAFC5R

Cu Κα (λ = 1.54178 A) is stable

120.2 °

Lorentz - polarization

Absorption (Transmission factors

0.87-1.00)

Total: 6520

Unique: 6520

Dissolution of the structure and purification

Number of observations (1> 3.0 σ (I)) 2154

Number of variables 443

Reflections / ratio of parameters 4.86

Residues: R; Rw 0.096; 0.093 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

In one example, the Type III desolvated crystalline form of lopinavir is obtained from acetonitrile. From all other solvents it was not possible to obtain a fully desolvated Type III crystalline form of lopinavir.

Type III desolvated crystalline forms of lopinavir are useful in the purification and isolation of lopinavir and in the preparation of pharmaceutical preparations for the administration of lopinavir.

The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing a Type III desolvated w form of lopinavir and differentiating Type III desolvated crystalline forms of lopinavir from other crystalline forms of lopinavir, with the exception of a Type III solvated crystalline form.

The type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of logishavir) also has the characteristic solid phase FT mid-infrared bands shown in Table 3. Table 3 shows the interval of peak positions for each of the 16 characteristic mid-infrared bands. solid phase FT w mid-infrared spectrum of type III desolvated crystalline form lopinavir. This means that the type III desolvated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in Table 3.

Most typical of Type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of lopinavir) are the positions of solid-phase FT mid-infrared bands for amide bonded carbonyl elongation. One strip is located in the interval 1655-1662 cm ⁴ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·················· Type III desolvated crystalline form of lopinavir. Often a second strip appears (in the range 1636-1647 cm < -1 ^> ) as the shoulder of the first strip, or it is not well distinguished from the first strip and is distinguished three times as a second strip. Any type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of lopinavir) will peak at a position in the range 1655-1662 cm ' ¹ and may also peak at a position in the range 1636-1647 cm' ¹ as a shoulder of peak position in the range 1655-1662 cm ^'1.

The solid phase FT medium infrared spectrum of the Type III desolvated crystalline form of lopinavir is shown in FIG. 21. The solid phase FT infrared spectrum in the near region of Type III desolvated crystalline form of lopinavir is shown in FIG. 23. Solid Phase 100 MHz Spectrum ¹³ The nuclear magnetic resonance of the type III desolvated crystalline form of lopinavir is shown in FIG. 24. A DSC thermogram of the type III desolvated crystalline form of lopinavir is shown in FIG. 25.

The DSC thermogram of the type III desolvated crystalline form of lopinavir shows a melting endotherm beginning at 95 ° C and a peak W at 98 ° C (ΔΗ = 18 J / g) when performing differential scanning colorimetry at a scan rate of 1 ° C / min up to 150 ° C for the sample, at losses of 0.0% of the original weight of the sample at heating from 1 ° C / min to 150 ° C

The positions of the two-theta angles of characteristic peaks in the X-ray powder diffraction profile of Type III desolvated crystalline lopinavir (including virtually pure Type III desolvated crystalline lopinavir) as shown in FIG. 23, ca: 4.85 ° ± 0.1 °, 6.39 ° ± · · · · · · · · · · · · · · · · · · · · · · ·

0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 °, and 17.70 ° ± 0.1 °.

In particular, Type III desolvated crystalline lopinavir (including virtually pure Type III desolvated crystalline lopinavir) is characterized by peaks in the powder X-ray diffraction profile having the two-theta angles positions shown in FIG. 23: 4.85 ° ± 0.1 °, 6.39 ° ± 0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 °, 17.70 ° ± 0.1 °, 18.70 ° ± 0.1 °, 20.68 ° ± 0.1 °, 20.92 ° ± 0.1 °, 22.06 ° ± 0.1 °, and 22.76 ° ± 0.1 °.

Separate X-ray crystallographic parameters and experimental details for Type III desolvated crystalline lopinavir

Experimental details

Crystal data Crystal system Grid parameters Orthorhombic a = 24.0465 (10) A b = 27.5018 (11) A c = 11.9744 (3) A V = 7918.9 (8) A ³ Space group With value P2221 (# 20) 8 Deale 1,055 g / cm ³

Intensity measurements

Diffractometer Radiation Nonius Kappa CCD Mo Κα (λ = 0.71073 A) Temperature room

max

61 °

Number of Reflections Measured Total: 28494

Unique: 5148

Dissolution of the structure and purification

Number of observations (Ι> 3.0 σ (I)) 4069

Number of variables Reflections / attitude of 442 parameters Residues: R; Rw 9.21 0.056; 0.116

In another method of the present invention, an unsolvated crystalline form of lopinavir is presented. For the purpose of identification, the unsolvated crystalline form of lopinavir of this method is designated Type IV.

The type IV unsolvated crystalline form of lopinavir is useful in purifying or isolating lopinavir and in the preparation of pharmaceutical preparations for the administration of lopinavir.

In the preferred method of Type IV, the unsolvated crystalline w form of lopinavir is substantially pure compared to other forms of lopinavir, including amorphous, hydrated forms, solvated forms and other unsolvated or desolvated forms.

The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing the Type IV unsolvated form of lopinavir and differentiating the Type IV unsolvated crystalline form of lopinavir from other crystalline forms of lopinavir.

·· ···· • ·· • • · • • · • · · • • « • · • • · • · • • · • • • • · · • · • • · • • · • · • · · • · • · • · · ·

Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) has the characteristic solid phase FT mid-infrared bands shown in Table 4. Table 4 shows the interval of peak positions for each of the 19 characteristic mid-infrared FT bands. medium infrared spectrum of type IV unsolvated crystalline form of lopinavir. This means that the Type IV unsolvated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in Table 4. When the solid-phase mid-infrared spectrum is obtained at a resolution of 4 cm-1, it can to be observed to peak at a position in one or more of the following additional characteristic bands: 1668-1674 cm ^_1 (strong), 1656 to 1662 cm-amplification), 1642-1648 cm ^'1 (strong). At higher resolution or after Fourier transform, these additional peaks are clearly distinguished.

Most typical of Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) are the positions of solid-phase FT medium infrared bands for amide bonded carbonyl elongation. These bands are located in the interval 1680-1685 cm ^'1 and 1625-1630 cm' ¹ for the Type IV unsolvated crystalline form of lopinavir. In addition, especially in high resolution, bands are located in the interval 1668-1674 cm ^'1, 1656-1662 cm' ¹ and 16421648 cm ^'1. Any Type IVI unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) will have a peak at a position in the range 1680-1685 cm ' ¹ and a peak at a position in the range 1625-1630 cm' ¹ and also z ft · »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Thus, there may be a peak in position in the interval 1668-1674 cm ' ¹ , a peak in the interval 1656-1662 cm ⁴ and a peak in the interval 1642-1648 cm' ¹ .

In addition, Type IVI unsolvated crystalline form lopinavir (including substantially purified Type IV unsolvated crystalline form lopinavir) is characterized by solid state IR peak position in any of the intervals: 780-784 cm ^'1, 764-768 cm' ¹ and 745 -749 cm ¹ .

Table 4

Peak position intervals for solid phase bands

FT medium infrared bands for Type IV unsolvated crystalline form of lopinavir

Minimum cm ' ¹ Maximum cm ' ¹ Intensity * 3433 3439 In 3415 3421 In 3406 3412 In 3338 3345 ss Chin- 3309 3315 In 3272 3278 In 3082 3089 Sl 3025 3030 Sl 2959 2965 In 2926 2932 Sl 2870 2875 Sl 1680 1685 p 1625 1630 MS 1514 1526 p

1451 · · · · · · · · · · · · · · · · · · · «* · · · · · · • · · · · · · · · · · · · · 4 · · · <· · · · 1456 SS 1306 1312 In 1189 1194 In 1089 1094 Sl 1044 1050 Sl

* Cl = weak; B = moderate; CC = medium strong; C = strong;

MS = very strong

Type IV unsolvated crystalline form of lopinavir has a solid-phase FT mid-infrared spectrum, a solid-phase FT ^W infrared spectrum in the near region, a powder X-ray diffraction pattern, a solid-phase 100 MHz spectrum ¹³ C nuclear magnetic resonance imaging (DSC), and a differential LC are shown in FIGS. 26, 27, 28, 29 and 30 respectively.

The positions of the two-theta angles of the characteristic peaks in the powder X-ray diffraction profile of type IV unsolvated crystalline lopinavir (including virtually pure Type IV unsolvated crystalline form V lopinavir) as shown in FIG. 28, ca: 6.85 ° ± 0.1 °, 9.14 ° ±

0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 ° and 18.53 ° ± 0.1 °.

In particular, Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) is characterized by peaks in the powder X-ray diffraction profile having the positions of the two-theta angles shown in FIG. 28: 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 10.80 ° ± 0.1 °, 12.04 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °,

4 « 4444 4 • 4 • 4 · • • • • 4 · 4 • · • · • 4 • • 4 • • · • • • • • • 4 • · • • e • • · • · • is 4 4 4 • · 4444

17.74 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.26 ° ± 0.1 °, 18.53 ° ± 0.1 °, 20.47 ° ± 0.1 ° and 25.35 ° ± 0.1 °.

The DSC thermogram of the Type IV unsolvated crystalline form of lopinavir shows a melting endotherm beginning at 117 ° C and a peak at 122 ° C (ΔΗ = 47 J / g) when performing differential scanning colorimetry at a scan rate of 1 ° C / min to 150 ° C.

The individual parameters for X-ray crystallography and the experimental details for Type IV unsolvated crystalline form of lopinavir are as follows:

Separate X-ray crystallographic parameters and experimental details for Type IV unsolvated crystalline lopinavir

Experimental details

Crystal data

Crystal system

Grid parameters

Space group

With value

Deale

Orthorhombic a = 15.065 (8) A b = 25.27 (1) A c = 9.732 (3) A V = 3704 (3) A ³ P2! 2i2i (# 20) 4

1.13 g / cm ³

Intensity measurements

Diffractometer

Radiation

Temperature

Rigaku AFC5R

Cu Κα (λ = 1.54178 A) is stable

• • • · • • ···· • • • ·· · • · • · • • * ·· • · • • • • • • • • • • · • · • • • • ·· • · ··· ·· ·· ····

120.21 °

2Θ max

Correction

Lorentz - polarization

Absorption (Transmission factors:

0.8362-09496)

Number of Reflections Measured Total: 3145

Dissolution of the structure and purification

Number of observations (Ι> 3.0 σ (I)) 1434

Number of variables 415

Reflections / ratio of parameters 3.46

Residues: R; Rw 0.081; 0.085

Type IV unsolvated crystalline form of lopinavir can be obtained from acetonitrile by slow cooling and slow ignition of a saturated solution or exposure of amorphous lopinavir to an atmosphere of acetonitrile. In addition, Type IV unsolvated lopinavir crystals may be added to the solution of lopinavir in acetonitrile to induce crystallization to give Type IV unsolvated lopinavir crystals.

The following examples can be used to further illustrate the method of the present invention for the preparation of new crystalline forms of lopinavir.

Example 1

Preparation of Type I highly hydrated crystalline form of lopinavir

A saturated solution of lopinavir in a mixture of 20 mL ethanol and 40 mL water was prepared at room temperature. The saturated solution was stirred at room temperature and water (54 mL) was slowly added using a syringe pump at a feed rate of 0.15 mL / min. Stirring overnight gave a precipitate (crystals) which was filtered.

Example 2

Preparation of Type I highly hydrated crystalline form of lopinavir

The NMR tube was filled with 1.75 mL of water. Subsequently, 0.5 mL of lopinavir solution in ethanol (99.482 mg / mL ethanol) was applied very carefully to the water layer. The tube was closed to prevent evaporation and was left unshaken. After about 30 days, crystals of type I hydrogenated crystalline form of lopinavir containing more than 0.5 molecules of water per molecule of lopinavir were obtained.

Example 3

Preparation of Type I highly hydrated crystalline form of lopinavir

Lopinavir (30 g) was dissolved in a mixture of 360 mL of deionized distilled water and 418 mL of ethanol 190 proof by heating with moderate stirring at about 60 ° C. The hot solution was filtered gravitationally to remove · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· undissolved material. The filtrate was slowly cooled with gentle stirring to room temperature at which point it was seeded with embryos of about 50 mg of the product of Example 1. The mixture was stirred at a moderate rate at room temperature for three days. The resulting mixture was filtered under vacuum. The filtered solid was transferred onto filter paper and all lumps were broken by gentle spatula manipulation. The solid was then transferred to a glass crystallization dish and placed in a desiccator over saturated sodium chloride solution to maintain a constant relative humidity of 75%. After drying for 12 days at room temperature (24 ± 1 ° C) and a relative humidity of 75%, about 20.5 g of the desired hydrate form of lopinavir was obtained. X-ray diffraction profile of a powder sample (FIG. 5). ¹³ C NMR spectrum of a solid at 100 MHz (FIG. 6). Solid phase FT in the near infrared region (FIG. 7). Solid phase FT in the mid-infrared region (FIG. 8). The product contained 4.3% volatile material according to thermo-gravimetric analysis.

Example 4

Obtaining a Type ϊ hydrated crystalline form of lopinavir containing about 0.5 molecules of water per molecule of lopinavir

The product of Example 3 (about 100 mg) was placed in an X-ray powder diffractometer holder, complete with a chamber for controlled sample atmosphere and heating. The sample was heated at HS / min to 30 ° C in · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Атмос атмос су су на атмос атмос. The conversion to the hemihydrate was performed for 60-90 min. Powder X-ray diffraction profile (FIG.

1) ·

Example 5

Preparation of Type I Hydrated Crystalline Form of lopinavir containing about 0.5 molecules of water per molecule of lopinavir

The product of Example 3 (1 g) was dispersed as a thin layer in a polypropylene weight canister and dried overnight in a vacuum oven at - 65 kPa and ambient temperature. The resulting hygroscopic product (lopinavir hemihydrate) was transferred into glass ampoules and dried again for 6 hours at about - 65 kPa and ambient temperature. The ampoules were then quickly sealed with polypropylene lids and stored in a desiccator over anhydrous calcium sulfate. ¹³ C NMR spectrum of a solid at 100 MHz (FIG. 2). Solid phase FT in the near infrared region (FIG. 3). Solid phase FT in the mid-infrared region (FIG. 4). The product contained 2% volatile material as determined by thermo-gravimetric analysis.

Example 6

Preparation of Type II isopropanol semisolvated crystalline form of lopinavir

Lopinavir (16 g) was dissolved in 50 mL of isopropanol by heating the mixture on a hot plate to boiling point with magnetic stirring. The solution was then cooled to room temperature. The solution was cooled to room temperature. · · · · · Temperature and a precipitate forms. The resulting mixture was stirred at room temperature for 24 hours with stirring sufficient to maintain the precipitate in suspension. The precipitate was collected by suction filtration and air-dried to give 9.9 g of Type II isopropanol semisolvate crystalline form of lopinavir. The thermogravimetry of the product indicated the presence of a volatile material corresponding to 1 mole of isopropanol for every two mole of lopinavir. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvate crystalline form of lopinavir Type II. Solid-phase FT in the mid-infrared region (FIG. 9). Solid phase FT in the near infrared region (FIG. 14).

Example 7

Preparation of Type II isopropanol solvate crystalline form of lopinavir (1.6% isopropanol by weight according to thermogravimetry)

Lopinavir (1 g) was suspended in 2.5 mL isopropanol in a glass ampoule containing four 4 mm diameter glass beads to improve stirring. The ampoule was closed with a lid and the suspension rotated in a drum at room temperature for 4 months. The suspension was then transferred to a Petri dish and the solvent was allowed to evaporate slowly. The Petri dish was then placed in a vacuum oven which was heated to 50 ° C and the sample was dried at -65 kPa at 50 ° C for 25 days to give the title compound. The product contained 1.6% volatile material according to thermogravimetry.

Example 8

Preparation of Type II isopropanol solvate crystalline form of lopinavir (2% isopropanol by weight according to thermogravimetry)

A sample of the product of Example 6 was washed with heptane, then dried for two days in a rotary evaporator. The residue was taken up in a Petri dish and dried in a vacuum oven, which was then heated to 50 ° C and the sample was dried at -65kPa at 50 ° C for 3 days to obtain the title compound. The product contained 2% volatile material according to thermogravimetry. Solid phase FT in the mid-infrared region (FIG. 10). Solid phase FT in the near infrared region (FIG. 15).

Example 9

Preparation of Type II ethyl acetate hemisolvate crystalline form of lopinavir

Example 9A

Preparation of crude lopinavir

Crude lopinavir prepared according to U.S. Patent No. 5,914,332 (Example 38) from (2S, 3S, 5S) -2-aminoH3-3-fluoro-CH-5- [2S- (1-tetrahydropyrimid-2-one) -3-methylbutanoyl] amino- The 1,6-diphenylhexane (S) -pyroglutamic acid salt (about 85 g, corrected for solvent content) was dissolved in 318.5 grams of ethyl acetate and the solution was concentrated to an oil in vacuo. The residue was dissolved in 225 grams of ethyl acetate, then concentrated twice to an oil in vacuo. The residue was dissolved in ethyl acetate (approximately 300 mL) at 65 ° C, filtered to remove any trace of undissolved solids and concentrated to a foam in vacuo. The foam was dissolved in 338 grams of ethyl acetate and this solution was divided into four equal portions.

Example 9 B.

C Obtaining Type II ethyl acetate hemisolvate crystalline form of lopinavir

Part of the lopinavir solution obtained in Example 9A was concentrated to an oil in vacuo, then dissolved in 50 mL absolute ethanol. The solvent was removed in vacuo. The residue was kept under vacuum with heating (approximately 5560 ° C) for an additional 30 minutes. The resulting foam was dissolved in ethyl acetate (87 mL) at room temperature. In less than five minutes of stirring, the solid phase was apparent. The resulting slurry was stirred for 16 hours, then diluted with 87 mL of heptanes. After three hours, solids were collected by filtration, washed with 36 mL of EtOAc / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 19.4 g of Type II ethyl acetate hemisolvate of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 11). Solid phase FT in the near infrared region (FIG. 16). The product contained 4.4% volatile material according to thermogravimetry.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 9 B.

Alternative preparation of Type II ethyl acetate hemisolvate crystalline form of lopinavir

Crude lopinavir prepared according to U.S. Patent No. 5,914,332 (Example 38) from (2S, 3S, 5S) -2-aminoHCO-3-benzylCH-5- [2S- (tetrahydropyrimid-2-one) -3-methyl butanoyl] amino The 1,6-diphenylhexane (s) pyroglutamic acid salt (about 20 g, corrected for solvent content) was dissolved in 118 grams of ethyl acetate and then concentrated to an oil in vacuo. The residue was dissolved in 95.7 grams of ethyl acetate at 46 ° C, then concentrated to an oil in vacuo. The residue was dissolved in 95.8 grams of ethyl acetate at 64 ° C. Karl Fischer moisture measurements showed less than 0.05% water. The product solution was cooled to 41 ° C and seeded with 0.20 g of the product of Example 9B. The solution was cooled to 35 ° C and stirred at this temperature for 1.25 hours. The resulting slurry was then cooled to 15 ° C for more than 10 minutes and stirred at 15-18 ° C for 1.5 hours. The solids were collected by filtration, washed with 13.3 grams of ethyl acetate and dried under vacuum at 56-58 ° C for 16 hours, yielding 12.3 g of Type II ethyl acetate hemisolvate of lopinavir.

Example 10A

Preparation of Type II ethyl acetate semi-solvate crystalline form of lopinavir (having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir according to thermogravimetry)

A portion of the lopinavir solution obtained in Example 9A was concentrated to an oil in vacuo, then dissolved in 50 ml.

mL of absolute ethanol. The solvent was removed in vacuo. The residue was kept under vacuum with heating (approximately 5560 ° C) for an additional 30 minutes. Crystalline embryos from the product of Example 9B were added to the foam obtained. The foam residue was dissolved in ethyl acetate (87 mL) at ambient temperature. In less than five minutes of stirring, the solid phase was apparent. The resulting slurry was stirred for 16 hours, then diluted with 87 mL of heptanes. After three hours, solids were collected by filtration, washed with 36 mL EtOAc / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 19.37 g of Type II ethyl acetate solvate of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 12). Solid phase FT in the near infrared region (FIG. 17). The product contained 1.7% volatile material according to thermogravimetry.

Example 10B

Alternative preparation of Type II-ethyl acetate solvate crystalline form of lopinavir (having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir according to thermogravimetry)

Crude lopinavir solution prepared according to U.S. Patent No. 5,914,332 (Example 2; coupling 17.0 g of (2S, 3S, 5S) -2 (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6diphenylhexane with 8.0 g of 28- (1-tetrahydropyrimid-2-one) -3methylbutanoic acid via EDAC / HOBT coupling) in isopropyl acetate (about 250mL) was concentrated to an oil in vacuo. The residue was dissolved in 250 mL of ethyl acetate and concentrated to a foam in vacuo. The foam was dissolved in 120 ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ML warm ethyl acetate. The solution was divided into three equal portions of 44.9 grams each. The solutions were cooled to room temperature and crystallization rapidly followed. One of these parts was stirred at room temperature overnight. The solids were collected by filtration, washed with 8 mL of ethyl acetate, then dried under vacuum at 22 ° C for 40 hours, then further dried for 44 hours under vacuum at 70 ° C to give 6.23 grams of Type II ethyl acetate solvate. lopinavir.

Example 11

Preparation of Type II hemisolvate crystalline form of lopinavir with chloroform

Lopinavir (10 g) was dissolved in 30 mL of chloroform. The solution was then heated to reflux on a hot magnetic stirring plate. After reducing the volume of the solution to about 1/2 of the initial volume, about 10 mL of n-heptane was added dropwise until the solution began to cloud. An additional 30 mL of chloroform was then added and the boiling continued until the volume was again about 1/2 of the initial volume. About 20 mL of chloroform was then added and the boiling continued until the volume was again about 1/2 of the initial volume. The mixture was then cooled slowly to room temperature and allowed to partially evaporate. After slow evaporation, a glassy residue with molasses consistency remains. This substance was mixed with about 20 mL of chloroform and heated on a hot plate. Then n-heptane was added dropwise until a precipitate formed. The precipitate was dissolved by reheating the mixture. The warm solution was transferred to a beaker that was

placed inside a jar containing about 20 mL of heptane and allowed to cool. After about 1 hour a thick solid precipitate formed. Most of the precipitate was redissolved by adding about 20 mL of chloroform to the contents of the beaker. After allowing this mixture to stand for about 1 hour, little needle-shaped crystals form. More heptane (about 40 mL) was added to the beaker containing the beaker and the jar was closed and left to stand. After a day, the beaker contained a large number of crystals. The crystals were collected by vacuum filtration. The crystalline mass was crushed carefully using a spatula and the crystals were washed with chloroform / heptane from the bank outside the beaker in which the crystals were grown. Thermogravimetry of the product indicates the presence of a volatile material corresponding to 1 mole of chloroform for every two mole of lopinavir. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvate crystalline form of lopinavir Type II. Solid phase FT in the mid-infrared region (FIG. 13). Solid phase FT in the near infrared region (FIG. 18).

Example 12

Preparation of Type III ethyl acetate solvated crystalline form of lopinavir

Lopinavir (7.03 g) was dissolved in ethyl acetate (33.11 g) at 71 ° C. The solution was cooled to 42 ° C for 45 minutes, with solids apparent. The sludge was cooled to 35 ° C for 30 minutes, then stirred for one hour. The slurry was then cooled to 15 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ ·· for 13 minutes and then stirred for one hour. Mixed heptanes (25.1 g) were added dropwise over 13 minutes. The resulting slurry was stirred for 30 minutes. The solids obtained were collected by filtration, washed with ethyl acetate / mixed heptanes (1: 1 v / v, 20 mL) and dried in vacuo at 62 ° C for 20 hours, yielding 6.4 g of the compound from the title. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was Type III solvated crystalline form of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 19). Solid phase FT in the near infrared region (FIG. 20). The product contains 2.3% volatile material according to thermogravimetry.

Example 13

Preparation of Type III ethyl acetate solvated crystalline form of lopinavir

Approximately 100 mg of lopinavir was dissolved in about 3 mL of ethyl acetate. About 3 mL of heptane was slowly and carefully added to this solution. After standing, crystals of type III solvated crystalline form of lopinavir by liquid diffusion crystallization.

Example 14

Preparation of Type III ethyl acetate solvated crystalline form of lopinavir

One portion of the lopinavir solution prepared in Example 9A was diluted with 14.8 grams of ethyl acetate and heated to 70-75 ° C, ··················································· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 75 grams of heptanes, maintaining an internal temperature higher than 70 ° C. The resulting solution was heated to 7 5 ° C for 15 minutes, then allowed to gradually cool to room temperature. After stirring overnight at room temperature, the solids were collected by filtration, washed with 36 mL of ethyl acetate / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 21.5 grams of the compound of the title.

W

Example 15

Preparation of Type III desolvated crystalline form of lopinavir

Lopinavir (5 g) was placed in a 100 mL beaker.

Acetonitrile was added in such a way that approximately 95% of lopinavir was dissolved. Some needle-shaped crystals remain undissolved. The beaker was placed inside a jar containing about 1 cm thick layer of anhydrous calcium sulphate (DRIERITE). The jar was closed and the material was left alone at room temperature. After staying overnight, a large amount of white crystalline material precipitated. The supernatant (about 6 mL) was decanted from the beaker. Fresh acetonitrile (3-4 mL) was added to the precipitate, which was then carefully ground with a spatula. The solid was collected by suction filtration and washed with about 1 mL of acetonitrile. The solid was transferred to a Petri dish and dried in vacuo at room temperature to obtain the Type III desolvated crystalline form of lopinavir. The product contained less than 0.05% ······ · ·· 9 ·· • · 9 9 9 9 9 9 9 99

9 9 9 9 9 9 99

9 9 9 9 9 9 9 9 99

9 9 9 9 9 9 9 99

99 999 99 99 9999 volatile material according to thermogravimetry. Solid-phase FT in the mid-infrared region (FIG. 21). Solid phase FT in the near infrared region (FIG. 22). X-ray diffraction profile of the powder sample (FIG. 23). ¹³ C NMR spectrum of the solid at 100 MHz (FIG. 24). DSC thermogram (FIG. 25).

Example 16

Preparation of Type IV unsolvated crystalline form of lopinavir

Lopinavir (amorphous, 1 g) was placed in a crystallization dish (A). This dish was placed in a larger crystallization dish (B) containing about 10 mL of acetonitrile and placed on a hot plate. Medium size crystallization dish (B) was reversed and placed above plate A, but inside plate B. A wide crystallization plate (D) was reversed and placed above plates A, B and C. The hot plate was warmed to about 35 °. C and then the hotplate was removed. The whole structure was then left to stand at room temperature for 10 days. After 10 days, all the acetonitrile was evaporated.

A portion of the crystalline product obtained (0.1 g) was mixed with acetonitrile (0.6 mL) and stirred for 1 hour. The mixture was filtered and the solid allowed to air to dry, yielding a Type IV unsolvated crystalline form of lopinavir.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 17

Preparation of Type IV unsolvated crystalline form of lopinavir

Lopinavir (259 g) was dissolved in 500 g of acetonitrile at 40-42 ° C. The cloudy solution was filtered through a 0.45 μ nylon membrane bottomed flask of 2 L, and to the solution were added a few crystals of the product of Example 16. The flask was placed on a rotary evaporator at 10-20 rpm ¹ overnight without heating and vacuum . As a result, a dense suspension of needle-like crystals is obtained. The slurry was cooled in an ice bath for 1 hour and then filtered on a desktop night filter in a nitrogen atmosphere and covered with nylon. The filter cake was washed with acetonitrile and dried to dryness under nitrogen for 30 minutes. The precipitate was then transferred to a crystallization vessel and dried for two days at 60-65 ° C at 20-21 "Hg in a nitrogen atmosphere, yielding 194.3 g of Type IV unsolvated crystalline form of lopinavir. The product was subjected to X-ray crystallographic diffractometry and was classified as Type IV unsolvated crystalline form of lopinavir by solid-state FT medium infrared spectroscopy (FIG. 26), solid-phase FT near-infrared spectra (FIG. 27), beams (FIG. 28), solid phase ¹³ C MHz at 100 MHz (FIG. 29) and DSC thermogram (FIG. 30) The product contains less than 0.1% volatile material determined by thermal gravimetric analysis.

When taken for the treatment of an illness caused by the AIDS virus, lopinavir is preferably used in

·· ···· • • • ·· · • ·· « • • • · • · • · • · • e • • • • • • · • · • · • ·· ··· is · • · ····

4: 1 combination with ritonavir (lopinavir: ritonavir). A preferred pharmaceutical preparation for the administration of lopinavir comprising a 4: 1 ratio of lopinavir: ritonavir has the following composition and is encapsulated in soft elastic gelatin capsules.

Lopinavir 133.3 mg Ritonavir Oleic acid, NF 33.3 mg 598.6 mg Propyl glycol, United States Pharmacopoeia Polyoxyl 35 castor oil, NF (Cremephor EL®) Purified Water, US Pharmacopoeia (distilled) 64.1 mg 21.4 mg 4.3 mg

If a hydrated or solvated crystalline form of lopinavir is used in the preparation, the amount of hydrated or solvated crystalline form of lopinavir is recalculated to take into account the amount of water or other solvent present in the crystalline form.

A preferred formulation can be prepared according to the following method.

The following protocol is used to obtain 1000 soft gelatin capsules:

Scale (mg / capsule) Name Quantity (g) Q.S. Nitrogen, N.F. Q.S. 578.6 Oleic acid, N.F. 578.6 33.3 Ritonavir 33.3 64.1 Propylene glycol, Pharmacopoeia of 64.1 USA

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

4.3 Water, purified, Pharmacopoeia of USA (Distilled) 4.3 133.3 Lopinavir 133.3 10.0 Oleic acid, N.F. 10.0 21.4 Polyoxyl 35 castor oil, NF 21.4 10.0 Oleic acid, N.F. 10.0

The mixing vessel and the appropriate container are purged with nitrogen.

The mixer was charged with 578.6 g of oleic acid. The mixer is J heated to 28 ° C (not exceeding 31 ° C) and stirring begins

33.3 g of ritonavir were then added to the oleic acid with continuous stirring. Propylene glycol and water are then added to the mixer and stirring is continued until the solution is clarified. 133.3 g of lopinavir are then added to the mixer and stirring is continued. Then 10 g of oleic acid are added to the mixer and stirring is continued until a clear solution is obtained. 21.4 g · were then added to the mixer; polyoxyl 35 castor oil NF, after stirring 10 g of oleic acid are added. The solution is stored at 2 - 8 ° C

I until encapsulation of the mixture. 0.855 g of solution are placed in each soft gelatin capsule and then the soft gelatin capsules are dried and stored at 2-8 ° C.

As used herein, the term "substantially pure" when used with respect to the crystalline form of lopinavir, refers to the crystalline form of lopinavir having more than 90% purity. This means that the crystalline form of lopinavir contains no more than about 10% of another compound and, in particular, does not contain more than about 10% of any other

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The form of lopinavir, such as amorphous lopinavir, solvated form, unsolvated form, and desolvated forms. In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 95% pure. This means that the crystalline form of lopinavir contains no more than about 5% of another compound and, in particular, does not contain more than about 5% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms. In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 97% pure. This means that the crystalline form of 'lopinavir does not contain more than about 3% of another compound and, in particular, does not contain more than about 3% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms .

In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 98% pure. This means that the crystalline form of lopinavir contains no more than about 2% of another compound and, in particular, does not contain more than about 2% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms.

In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 99% pure. This means that the crystalline form of lopinavir contains no more than about 1% of another compound and, in particular, does not contain more than about 1% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms.

• ·

Powder X-ray diffraction analysis was performed as follows. X-ray diffraction samples were prepared by spreading a powdered substance (powdered fine powder in a pestle mortar or shrink glass microscope slides for a limited amount) into a thin layer on a sample pad and gently pressing the sample microscopically. Samples were analyzed in one of three configurations: circular bulk

a support, a quartz plate for the control zero, or a hot plate (similar to the placement of the control plate). X-ray diffraction was performed using an XDS 2000 ΘΙΘ diffractometer (Scintag; 2 kW normal-focus X-ray tube with liquid nitrogen or Peltier cooled solid phase detector; 45 kV and 30 - 40th, X-ray source: Cu-Kal: X-ray source: Cu) ; range: 2.00-40.00 ° two theta; scan rate: 0.5 or 2 degrees / minute), XRD-6000 diffractometer (Schimadzu, fine-focus X-ray tube with Nal scintillation detector, 40-45 kV and 30-40th, source X-rays: CuKal; Range: 2.00-40.00 ° two theta; Scanning speed: 0.5 or 2 degrees / minute) or 1-2 X-ray diffraction odometer (Nicolet; scintillation detector; 50 kV and 30 ta, X-ray source: Cu-Kal; range: 2.00-40.00 ° two theta; scan rate: 0.5 or 2 degrees / minute). The relative humidity of the sample in the hot plate can be controlled using a relative humidity generator (model RH 200, VTI Corp.).

The positions of the peaks of the characteristic X-ray diffraction profile are reported for polymorphs with respect to the positions of the angles (two theta) with a tolerable variability of ± OG. Allowable variability is determined by the Pharmacopoeia of · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

United States, pp. 1843-1844 (1995). A ± 0.1 ° variability is used when comparing two powder diffraction profiles. In practice, if the profile of the diffraction peak of one profile falls within the interval of angular positions (two theta), which is the measured peak position ± 0.1 ° and the peak of the diffraction profile of the print profile falls within the interval of angular positions (two theta), which is the measured peak position ± 0.1 ° and if these intervals of peak positions overlap, then the two peaks are considered to have identical angular positions (two theta). d For example, if a diffraction profile peak from one profile is determined to have a peak position of 5.20 ° for comparability, the allowable variability allows a peak to be set in the range 5.10 - 5.30 °. If a peak position of 5.35 ° is set for the comparative peak from the other diffraction profile, for the sake of comparability, the allowable variability allows the peak to be set in the range 5.25 - 5.45 °. Since there is an overlap between the two intervals of the peak positions (ie 5.10 ° - 5.30 ° and 5.25 ° - 5.45 °), the two peaks that are compared can be considered as having the same angular position (two theta) .

έ ^{w The} solid-state nuclear magnetic resonance analysis of the samples was performed as follows. An apparatus was used

Bruker AMX-400 with the following parameters: CP-MAS (cross polarized magnetic angular rotation); the frequency of the ¹³ C spectrometer was 100.6 MHz; pulse sequence - VA-CP2LEV; contact time was 2.5 milliseconds; rotation speed - 700 Hz; recycling delay time of 5.0 sec .; 3000 scans).

The FT near-infrared sample analysis was performed as follows. Samples were analyzed as undiluted

Powders contained in a transparent glass vial. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · It was used Nicolet Magna System 750 FT-IR spectrometer c handler Nicolet SablR c fiberoptic probe c diffuse reflectance in the near infrared region with the following parameters: detector PbS, prism CaF2, number of scans of sample - 16, resolution 8 cm ^'1.

The FT average infrared analysis of the samples was performed as follows. Samples were analyzed as undiluted powders. A Nicolet Magna System 750 FT-IR spectrometer with a Nicolet NIC-PLAN microscope with a MCT-A detector with liquid nitrogen cooling was used. The samples were placed in a 13 mm x 1 mm BaF2 sample disk mount. 64 scans were carried out at a resolution of 4 cm ' ¹ .

The differential scanning calorimetric analysis of the samples was performed as follows. A Differential Scanning Calorimetry Model 2920 AT.A Instruments with DSC Cell, TA Instrument with Thermal Solution Data Analysis Software, Version 2.3 was used. The analysis parameters are: Sample size: 4-10 mg, placed in an aluminum vial sealed with a needle lid, heating rate: 1 ° C / min in a nitrogen atmosphere (40 - 50 mL / min).

Thermal gravimetric analysis was performed by heating the sample from room temperature to 200 ° C at a heating rate of 1 ° C or 5 ° C / minute.

The above examples illustrate the invention without limiting the invention to the examples described. Variations and changes that are apparent to anyone experienced in the prior art fall within the scope and nature of the present invention, which is defined by the following patent

Claims (23)

This invention relates to novel crystalline forms of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- (2- (1tetrahydropyrimid-2-one) -3-methylbutanoyl) amino -1,6diphenylhexane (also known as lopinavir) and methods for their preparation. The new crystalline forms of the invention may be used to purify or isolate lopinavir or to prepare pharmaceutical preparations for the administration of lopinavir. BACKGROUND OF THE INVENTION Human immunodeficiency virus (HIV) protease inhibitors were approved several years ago for use in the treatment of HIV infections. A particularly effective and recently approved HIV protease inhibitor is (2S, 3S, 5S) -2 (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- (2- (1-tetrahydropyrimid-2-one) -3-methylbutanoyl) amino-1,6-diphenylhexane (also known as lopinavir). Lopinavir is known to have the ability to inhibit HIV protease and inhibit HIV infection. Lopinavir is particularly effective for inhibiting HIV protease and inhibiting HIV infection when co-administered with ritonavir. Lopinavir in combination with ritonavir is also particularly effective in inhibiting HIV infection when used together with one or more reverse transcriptase inhibitors and / or one or more other protease inhibitors. Lopinavir and methods for its preparation are described in U.S. Patent No. 5,914,332 of June 22, 1999, which is incorporated herein by reference. This patent also describes methods for the preparation of amorphous lopinavir. Pharmaceutical preparations containing lopinavir or its pharmaceutically acceptable salts are described in U.S. Patent No. 5,914,332 of June 22, 1999; U.S. Patent Application No. 08 / 966,495, filed Nov. 7, 1997; U.S. Provisional Patent Application No. 60 / 177,020, filed Jan. 19, 2000, and U.S. Patent Application No. 09 / 487,739, filed Jan. 19, 2000, all of which are incorporated herein by reference. It has been unexpectedly discovered that lopinavir can be prepared and isolated individually by any one of a plurality of crystalline forms. » Short description of the figures FIG. 1 is the X-ray powder diffraction profile of a Type I hydrated crystalline form of lopinavir comprising about 0.5 molecules of water per molecule of lopinavir. • «· · · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · FIG. 2 is a 100 MHz solid-phase ¹³ C spectrum of the Type I hydrated crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir. FIG. 3 is the FT near infrared solid phase spectrum of a Type I hydrated crystalline form of lopinavir, comprising about 0.5 molecule mode for a lopinavir molecule. FIG. 4 is the FT average type I infrared solid phase spectrum of a hydrated crystalline form of lopinavir, comprising about 0.5 molecules of mode for a lopinavir molecule. FIG. 5 is a powder X-ray diffraction pattern of Type I, a more hydrated crystalline form of lopinavir. FIG. 6 is the 100 MHz solid phase spectrum of the Type I nuclear resonance type I more hydrated crystalline form of lopinavir. FIG. 7 is the FT near Type I infrared solid phase spectrum of the more hydrated crystalline form of lopinavir. FIG. 8 is the FT average Type I infrared solid phase spectrum of the more hydrated crystalline form of lopinavir. FIG. 9 is the FT average type II infrared solid phase spectrum of isopropanol hemisolvated crystalline form of lopinavir. FIG. 10 is the FT average type II infrared solid phase spectrum of an isopropanol solvated crystalline form of lopinavir having about 2% solvent in thermal gravimetry. FIG. 11 is the FT mean type II infrared solid phase ethyl acetate hemisolvated crystalline form of lopinavir. FIG. 12 is the FT average solid phase infrared spectrum of Type II ethyl acetate solvated crystalline form of lopinavir having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir by thermal gravimetry. FIG. 13 is the FT mean solid-phase spectrum of the Type P chloroform hemisolvated crystalline form of lopinavir. FIG. 14 is the FT near infrared solid phase spectrum of type II isopropanol hemisolvated crystalline form of lopinavir. FIG. 15 is the FT near infrared solid phase spectrum of type II isopropanol solvated crystalline form of lopinavir having about 2% solvent in thermal gravimetry. FIG. 16 is the FT near infrared solid phase spectrum of type II ethyl acetate hemisolvated crystalline form of lopinavir. FIG. 17 is the FT near infrared solid phase spectrum of type II ethyl acetate solvated crystalline form of lopinavir having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir by thermal gravimetry. FIG. 18 is the FT near-infrared solid phase spectrum of type II chloroform hemisolvated crystalline form of lopinavir. FIG. 19 is the FT mid-infrared solid phase spectrum of type III ethyl acetate solvated crystalline form of lopinavir. FIG. 20 is the FT near infrared solid phase spectrum of type III ethyl acetate solvated crystalline form of lopinavir. FIG. 21 is the FT average Type III infrared solid phase spectrum of a desolvated crystalline form of lopinavir. • · · · · · · · · · · · · · · · · · · · · · · · · · · · · 1 ··· · · · · · · 99 ··· ·· ······ FIG. 22 is the FT near infrared solid phase spectrum of Type III desolvated crystalline form of lopinavir. FIG. 23 is the powder X-ray diffraction profile of type III desolvated crystalline form of lopinavir. . FIG. 24 is the 100 MHz solid phase ¹³ C spectrum of type III desolvated crystalline form of lopinavir. FIG. 25 is a differential scanning colorimetric (DSC) thermogram of a Type III desolvated crystalline form of lopinavir. FIG. 26 is the FT average solid phase infrared spectrum of Type IV non-solvated crystalline form of lopinavir. FIG. 27 is the FT near infrared solid phase spectrum of Type IV non-solvated crystalline form of lopinavir. FIG. 28 is the powder X-ray diffraction profile of Type IV non-solvated crystalline form of lopinavir. FIG. 29 is the 100 MHz solid phase spectrum of ¹³ C Type IV non-solvated crystalline form of lopinavir. FIG. 30 is a differential scanning colorimetric (DSC) thermogram of a Type IV non-solvated crystalline form of lopinavir. FIG. 31 is the powder X-ray diffraction profile of type III solvated (ethyl acetate) crystalline form of lopinavir. 'W · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · * · · · · · · · · · · · · · · · · · · Description of the invention According to the present invention, there are new crystalline forms of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- (2- (1 tetrahydropyrimid-2-one) -3-methylbutanoyl) amino -1,6diphenylhexane (lopinavir). According to one method of the present invention there are hydrated crystalline forms of lopinavir. To identify them, hydrated crystalline forms referred to as Type I. Type I hydrated crystalline forms of lopinavir include from about 0.5 molecules of water per molecule of lopinavir to about 2 molecules of water per molecule of lopinavir. Type I hydrated crystalline forms of lopinavir are used in the purification or isolation of lopinavir during the final steps of the lopinavir production process and in the preparation of pharmaceutical preparations for the administration of lopinavir. The type I hydrated crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, is hygroscopic. Therefore, while not stored at conditions of about 0% relative humidity, the Type I hydrated crystalline form of lopinavir contains more than 0.5 molecules of water per molecule of lopinavir. If a hydrated crystalline form of lopinavir of Type I is dehydrated to less than 0.5 molecules of water per molecule of lopinavir, amorphous lopinavir is obtained. Because Type I hydrated crystalline forms of lopinavir, comprising 0.5 molecules of water for the lopinavir molecule and about 2 molecules of water for the lopinavir molecule, represent, respectively, the lower and upper bounds of the solvation water observed for the crystalline hydrated forms of lopinavir Type I, the water content the crystalline form can vary in? * '· Whose range within this range depends on the temperature and water content of the crystalline environment. The term "Type I more hydrated crystalline form" will be used herein to refer to Type I hydrated crystalline forms of lopinavir containing from more than 0.5 molecules of water per molecule of lopinavir to about 2 molecules of water per molecule of lopinavir. Specifically, Type I, the more hydrated crystalline form of lopinavir contains from about 0.75 to about 1.9 molecules of water per molecule of lopinavir. In particular, the Type I more hydrated crystalline form of lopinavir contains from about 1.0 to about 1.8 molecules of water per molecule of lopinavir. In a preferred method, Type I hydrated crystalline forms of lopinavir are substantially pure as compared to other forms of lopinavir, including amorphous, solvated forms, unsolvated and desolvated forms. It has been found that the FT mid-infrared solid phase spectrum is a means of characterizing Type I hydrated crystalline forms of lopinavir and distinguishing hydrated crystal forms from other crystalline forms of lopinavir. Type I hydrated crystalline forms of lopinavir (including virtually pure Type I hydrated crystalline forms of lopinavir) have the characteristic FT mid-infrared solid phase bands shown in Table 1. Table 1 shows the interval of peak positions for each of the 17 characteristic mid-infrared mid-infrared bands. solid phase spectrum of type I hydrated crystalline forms of lopinavir. This means that any Type I hydrated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in the Table 1. Most typical of Type I hydrated crystalline lopinavir forms (including virtually pure Type I hydrated crystalline lopinavir forms) are FT positions of mid-infrared solid phase bands for amide bonded carbonyl elongation. These bands are located in the range 1652-1666 cm &lt; -1 & gt ^; and 1606-1615 cm &lt; -1 ^&gt; for Type I hydrated crystalline forms of lopinavir. Any Type I hydrated crystalline form lopinavir (including substantially pure Type I hydrated crystalline forms lopinavir) will have a peak at a position in the range of 1652-1666 cm ^'1 and peak position in the range 1606-1615 cm' ^1. Type I hydrated crystalline forms of lopinavir (including virtually pure Type I hydrated crystalline forms of lopinavir) are further characterized by an infrared solid phase peak at a position within each of the intervals 778-783 cm ⁴ , 765-769 cm ⁴ , 755-759 cm ⁴ and 738-742 cm ⁴ . • · · · · · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 9999 Table 1 Solid-state FT peak position intervals of mid-infrared bands for Type I hydrated crystalline lopinavir Minimum cm ' ¹ Maximum cm ' ¹ Intensity * 3495 3505 Sl / absent 3371 3386 C / SS 3281 3299 SS 3058 3064 Sl 3024 3031 Sl 2958 2967 In 2926 2938 Sl 2868 2875 Sl 1652 1666 MS 1606 1615 C / SS 1524 1532 p 1450 1456 SS 1404 1410 Cl / MSl 1304 1311 SS 1187 1197 SS 1089 1094 In 1048 1056 Sl * Cl = weak; B = moderate; CC = medium strong; C = strong; MS = very strong ·· ·· ··· ·· ·· ···· Type I crystalline form of lopinavir comprising about 0.5 molecules of water per molecule of lopinavir has a powder X-ray diffraction profile, which is presented in FIG. 1. The type I crystalline form of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, has a solid-phase ¹³ C nuclear magnetic resonance spectrum, FT near infrared spectrum and FT medium infrared spectrum, which are presented in Figs. 2, 3 and 4. The sample from which the infrared and nuclear magnetic resonance spectra are obtained may contain slightly more than 0.5 molecules of water per molecule of lopinavir due to the hygroscopicity of the crystalline form when the hydration level is about 0.5 molecules water for the lopinavir molecule. Positions of two-theta angles of characteristic peaks in the X-ray powder diffraction pattern of Type I hydrated crystalline lopinavir containing about 0.5 molecules of water for the lopinavir molecule (including virtually pure Type I hydrated crystalline forms of lopinavir, including 0.5 molecules of water for the lopinavir molecule) as shown in FIG. 1, ca: 7.25 ° ± 0.1 °, 8.53 ° + 0.1 °, 10.46 ° ± 0.1 °, 11.05 ° ± 0.1 °, 11.71 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.30 ° + 0.1 °, 16.67 ° + 0.1 °, 17.32 ° ± 0.1 °, 19.10 ° ± 0.1 °, 19.57 ° ± 0.1 °, 21.24 ° ± 0.1 °, 21.84 ° ± 0.1 ° and 22.46 ° ± 0.1 °. Type I hydrated crystalline forms of lopinavir, comprising about 0.5 molecules of water per molecule of lopinavir, can be obtained from a solution or suspension in water, or from solutions in mixtures of water and water-soluble organic solvents. Examples of water-soluble organic solvents are C1-C4 alcohols such as methanol, ethanol and the like; acetonitrile; and similar. The amount of water in mixtures of water and water-soluble organic solvents can range from about 10% by volume to about 90% by volume (in particular from about 40% to about 60% by volume). In a preferred Type I method, the more hydrated crystalline form of lopinavir can be obtained by crystallizing a hydrated form of lopinavir from a warm solution in a mixture of water and ethanol, followed by prolonged exposure in an environment with increased relative humidity. In addition, a Type I more hydrated crystalline form of lopinavir can be obtained by hydrating a Type I hemihydrated crystalline form of lopinavir at elevated relative humidity (e.g., at a relative humidity of about 20% or more). Type I, the more hydrated crystalline form of lopinavir has a powder X-ray diffraction profile, solid-phase ¹³ C nuclear resonance, solid-phase FT near-infrared, and solid-phase FT mid-infrared spectra, respectively. 5,6,7 and 8. Positions of the two-theta angles of characteristic peaks in the X-ray powder diffraction profile of Type I more hydrated crystalline lopinavir (including actually pure Type I more hydrated crystalline lopinavir), as shown in FIG. . 5, ca: 3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.57 ° + 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° ± 0.1 ° and 22.74 ° ± 0.1 °. In particular, Type I more hydrated crystalline lopinavir (including the virtually pure Type I more hydrated crystalline lopinavir) is characterized by peaks in the powder X-ray diffraction pattern having positions at two-theta angles, shown in FIG. 5: 3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.06 ° ± 0.1 °, 15.57 ° ± 0.1 °, 16.49 ° ± 0.1 °, 17.51 ° ± 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° + 0.1 °, 21.73 ° ± 0.1 ° and 22.74 ° ± 0.1 °. The individual parameters for X-ray crystallography and the experimental details for Type I more hydrated crystalline form of lopinavir are as follows: Separate parameters for X-ray crystallography and experimental details for Type I more hydrated crystalline lopinavir Experimental details Crystal data Crystal System Grid parameters Space group With value Deale Monoclinic a = 46.922 (2) A b = 13.9945 (4) A c = 11.7231 (4) A β = 105.605 (1) ° V = 7414.2 (4) A ³ C2 (# 5) 1.19 g / cm ³ Intensity measurements Bruker SMART diffractometer ·· ···· Radiation Temperature 20x Correction Number of Reflections Measured • · · ······ The mo Κα (λ = 0.7107 A) is stable 46.6 ° Lorentz - polarization Total: 27795 Dissolution of the structure and purification Number of observations (Ι> 3.0 σ (I)) 5368 Number of variables 932 Reflections / attitude of W * · 'parameters 5.76 Residues: R; Rw 0.107; 0.128 In two other methods of the present invention crystalline forms of lopinavir are solvated. Based on a single determination of X-ray crystal structure, the first method of solvated crystalline forms of lopinavir comprises a crystal structure in which clusters of lopinavir molecules bind to each other through hydrogen bonds and are arranged along the short crystallographic axis. Solvent molecules do not play a role in the hydrogen bond, but simply fill pockets that exist between the clusters of lopinavir molecules. For identification purposes, the solvated crystalline lopinavir forms of this method are designated Type II. Based on the single determination of X-ray crystal structure, the second method of solvated crystalline forms of lopinavir involves a crystal structure in which the lopinavir molecules are bonded to hydrogen bonded sheets, the sheets with ····· · ·· · · * • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hydrogen-coupled lopinavir molecules are twisted, forming channels that are filled with variable amounts of solvent molecules. Solvent molecules do not play a role in the hydrogen bond in the second method of solvated crystalline lopinavir. For the purpose of identification, solvated crystalline forms of lopinavir by this method are referred to as Type III. Type II Type II solvated crystalline forms of lopinavir are used to prepare or isolate lopinavir during the final steps of the lopinavir production method. Type II solvated crystalline forms of lopinavir are particularly useful for the preparation of crystalline lopinavir, which is free of, or has greatly reduced amounts of, the various impurities that are obtained by the method of preparation of lopinavir. Type P solvated crystalline forms of lopinavir are typical hemisolvates. In other words, for each asymmetric unit of the crystal there are two molecules of lopinavir and one molecule of solvent. Low levels of solvation are also possible. Type II solvated crystalline forms of lopinavir can be partially desolvated by heating under vacuum. However, if more than about 75% of the maximum permissible solvent is removed (the maximum permissible is hemisolvated), amorphous lopinavir is obtained. Therefore, type II solvated crystalline forms of lopinavir range from about 0.125 solvent molecules per molecule lopinavir to about 0.5 solvent molecules per molecule lopinavir. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ · ·· f ·· · »* ··· ♦♦ Type II solvated crystalline forms of lopinavir comprise relatively small polar organic solvents. Examples of such relatively small polar organic solvents are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-amyl alcohol, isoamyl alcohol, t-pentanol, ethyl acetate, acetone, tetrahydrofuran, methane chloride, propylene glycol, methyl ethyl ketone, dimethyl sulfoxide and the like. In the preferred Type II method, the solvated crystalline forms of lopinavir are substantially pure compared to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, non-solvated and desolvated forms. The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing Type II solvated crystalline forms of lopinavir and differentiating Type II solvated crystal forms from other crystalline forms of lopinavir. Type II solvated crystalline forms of lopinavir (including virtually pure Type II solvated crystalline ** forms of lopinavir) have the characteristic solid phase FT mid-infrared bands shown in Table 2. Table 2 shows the interval of peak positions for each of the 18 characteristic mid-infrared solid-phase bands. FT mean infrared spectrum of type II solvated crystalline forms of lopinavir. This means that any type II solvated crystalline form of lopinavir will have a position peak within the interval (minimum to maximum) for each of the peaks shown in Table 2. * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Most typical of Type II solvated crystalline lopinavir forms (including virtually pure Type II solvated crystalline lopinavir forms) are the positions of solid phase FT mid-infrared bands for amide bonded carbonyl elongation. These bands are located in the range 1661-1673 cm &lt; -1 &gt; 1645-1653 cm &lt; -1 ^&gt; and 1619-1629 cm &lt; ¹ & gt ^; for Type II solvated crystalline forms of lopinavir. Any type II solvated crystalline form of lopinavir (including virtually pure Type II solvated crystalline forms of lopinavir) will have a peak at a position in the range 1661-1673 cm ' ¹ , a peak at a position in the range 1645-1653 cm' ¹ and a peak at a position at interval 1619-1629 cm ' ¹ . Type II solvated crystalline forms lopinavir (including substantially pure Type II solvated crystalline forms lopinavir) is further characterized by an infrared solid-phase peak position within each of the intervals 776781 cm ^'1, 767-771 cm' ^1, 747-758 cm ⁴ and 742-746 cm ⁴ . • 9 ··· • »• · · • * • ·> ·· 9 * • • 9 « 9 • · 4 • · · 9 • 9 9 · • · · • · • • • · » • · 9 • 9 · · · • · ···· Table 2 Peak position intervals for solid-phase FT mid-infrared bands for Type II solvated crystalline lopinavir Minimum cm ' ¹ Maximum cm ' ¹ Intensity * * 3391 3415 In 3324 3340 SS 3057 3063 Sl 3023 3029 Sl 2961 2970 In 2913 2938 Sl 2866 2879 Sl 1661 1673 P 1645 1653 P 1619 1629 MS 1540 1548 SS 1514 1522 p 1450 1456 SS 1418 1426 In 1302 1309 In 1181 1193 SS 1089 1095 In 1045 1056 Sl Cl = weak; B = moderate; SS = average strong; ( = strong; MS = very strong ·· ··· ♦ e · ··· • · · ·· · V ·· • «· ·· • ♦ · · ·· λ ·· ·· ······ The solid-phase FT medium infrared spectra of the Type II solvated crystalline forms of lopinavir (isopropanol, ethyl acetate and chloroform) are given in Figs. 9, 10, 11, 12 and 13. The solid phase FT near-infrared spectra of the Type II solvated crystalline forms of lopinavir (isopropanol, ethyl acetate and chloroform) are given in Figs. 14, 15, 16, 17 and 18. Type II solvated crystalline forms of lopinavir can be prepared by suspending excess solid lopinavir in the solvent and allowing the suspension to equilibrate over time. The Type II solvated crystalline form of lopinavir was then isolated by filtration. Type II solvated crystalline forms of lopinavir can also be obtained by slow evaporation of the solvent from a solution of lopinavir. The Type II solvated crystalline form of lopinavir was then isolated by filtration. Type II solvated crystalline forms of lopinavir can also be prepared by slowly adding an anti-solvent to a heated solution of lopinavir in the solvent, thus causing crystallization. The Type II solvated crystalline form of lopinavir was then isolated by filtration. The individual X-ray crystallographic parameters and the experimental details for Type II ethyl acetate hemisolvated crystalline lopinavir and Type P chloroform hemisolvated crystalline lopinavir are as follows: Separate X-ray crystallographic parameters and experimental details for Type II etmlacetia hemisolvated crystalline form lopinavir Experimental details Crystal data Crystal system Grid parameters Space group With value Deale Monoclinic a = 11.3456 (1) A b = 33.9490 (2) A c = 9.8641 (2) A β = 89.930 (1) ° V = 3799.37 (7) A ³ P21 (# 4) 1.18 g / cm ³ Intensity measurements Diffractometer Radiation Temperature 20 things Correction Number of reflections measured Bruker SMART Mo Κα (λ = 0.7107 A) is stable 46.7 ° Lorentz - polarization Total: 14824 Unique: 5211 Dissolution of the structure and purification Observation count (1> 3.0 σ (I)) 4411 Number of variables 882 Reflections / ratio of parameters 5.0 Residues: R; Rw 0.104; 0.099 • «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Separate X-Ray Crystallographic Parameters and Experimental Details for Type II Chloroform HemisolvaLopinavir Crystal Crystal Form Experimental details Crystal data Crystal System Grid parameters Space group With value Deale Orthorhombic a = 9.7703 (51) A b = 33.410 (2) A c = 11.4874 (6) A V = 3749.8 (3) A ³ P21212 (# 18) 4 1.22 g / cm ³ Intensity measurements Diffractometer Radiation Temperature 20 things Correction Number of reflections measured Bruker SMART Mo Κα (λ = 0.7107 A) is stable 46.6 ° Lorentz - polarization Total: 14960 Unique: 4359 Dissolution of the structure and purification Number of observations (Ι> 3.0 σ (I)) 4234 Number of variables 438 Reflections / ratio of parameters 9.67 Residues: R; Rw 0.094; 0.104 Type III Type III solvated crystalline forms of lopinavir are useful in purifying and isolating lopinavir in the last steps of the lopinavir production process. Type III solvated crystalline forms of lopinavir are particularly useful for the preparation of crystalline lopinavir, which is free-form or has greatly reduced amounts of different impurities resulting from the method of preparation of lopinavir. Type III solvated crystalline forms of lopinavir are thermodynamically stable crystalline forms isolated from solvents, which generally include hydrophobic organic solvents or solvents that are too large to match the crystal lattice of Type II solvated crystalline forms of lopinavir. Type III solvated crystalline forms of lopinavir include solvents including n-hexanol, pctanol, 3-ethyl-3-pentanol, polyethylene glycol, ethyl acetate, isopropyl acetate, n-butyl acetate, glyceryl triacetate, acetone, methyl 2-isobutyl ketone 4-dimethylpentanone, alpha-tetralone, methyl t-butyl ether, 2,2,4,4-tetramethyltetrahydrofuran, isosorbide dimethyl ether, toluene, tetralin, nitrobenzene, p-xylene, sulfolane, hexane, heptane, decalin, oleic acid . In a preferred method, type III solvated crystals of lopinavir form are virtually pure compared to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, unsolvated and dissolved forms. The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing Type III solvated forms of lopinavir from other crystalline forms of lopinavir. Type III solvated crystalline forms of lopinavir (including virtually pure Type III solvated crystals of lopinavir) have the characteristic solid phase FT mid-infrared spectrum shown in Table 3. Table 3 shows the range of peak positions for each of the 16 characteristic mid-infrared bands. of solid phase FT mid-infrared spectrum of type III solvated crystalline forms of lopinavir. This means that each Type III solvated crystalline form of lopinavir will have a peak at a position in the range (minimum to maximum) for each of the peaks shown in Table 3. The most characteristic type III solvated crystalline form of lopinavir (including virtually pure Type III solvated crystalline form of lopinavir) are the positions of solid-weight FT mid-infrared bands for amide coupled carbonyl elongation. The band is localized in the range 1655 - 1662 cm &lt; -1 ^&gt; for Type III solvated crystalline forms of lopinavir. Often, a second strip is located in the range 1636-1647 cm ¹ for Type III solvated crystalline forms of lopinavir. However, in some cases, the second strip (in the range 1636-1647 cm &lt; -1 ^&gt; ) appears as a shoulder of the first strip or is not sufficiently separated from the first strip to be distinguished as a second strip. Each Type III solvated crystalline form of lopinavir (including virtually pure Type III solvated crystalline form of lopinavir) will have a peak in position in the range 1655-1662 cm ' ¹ and may also have a peak in position in the range 1636 1647 cm' ¹ . Type III solvated crystalline forms of lopinavir (including fastically pure Type III solvated crystalline forms of lopinavir) are further characterized by solid-phase infrared peak at position in the ranges 772-776 cm '\ 766-770 cm' ¹ and 743-747 cm ' ¹ . The positions of the two theta angles of characteristic peaks in the X-ray powder diffraction profile of a Type III solvilane (ethyl acetate) crystalline form of lopinavir (including virtually pure Type III solvate (ethyl acetate) crystalline form of lopinavir) FIG. 31 are: 4-85 ° ± 0.1 °, 6.52 ° ± 0.1 °, 7.32 ⁰ ± 0.1 °, 12.82 ° ± 0.1 °, 12.96 ° ± 0.1 °, 16.49 ° ± 0.1 °, and 19.31 ° ± 0.1 °. Table 3 Peak position intervals for solid-phase FT mid-infrared bands for Type III solvated and desolvated crystalline forms of lopinavir Minimum cm ⁴ Maximum cm ⁴ Intensity * 3394 3405 P 3278 3302 SS 3061 3071 Sl 3024 3033 Sl 2954 2965 In 2924 2936 Sl 2853 2872 Sl 1655 1662 MS 1636 1647 p 1517 1525 p 1501 1513 SS 1450 1455 SS 1300 1309 SS 1193 1200 SS 1090 1098 Sl 1051 1057 In · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· ·· ··· ·· ·· ···· * Sl = weak; B = moderate; CC = medium strong; C = strong; MS = very strong The solid phase FT medium infrared spectrum of type III solvated with ethyl acetate crystalline form of lopinavir is shown in FIG. 19. The solid phase FT infrared spectrum in the near region of Type III ethyl acetate solvated crystalline form of lopinavir is shown in FIG. 20. Type III solvated crystalline forms of lopinavir can be prepared by suspending excess solid lopinavir in a solvent and allowing the suspension to equilibrate for some time. The Type III solvated crystalline form of lopinavir was then isolated by filtration. The type III solvated crystalline form of lopinavir can also be obtained by cooling a saturated solution of lopinavir Type III solvated crystalline forms of lopinavir can also be prepared by allowing the solvent to slowly evaporate from the lopinavir solution. The Type III V solvated crystalline forms of lopinavir were then isolated by filtration. Type III solvated crystalline forms of lopinavir can also be prepared by slowly adding an anti-solvent to the heated solution of lopinavir in a solvent and thus induce crystallization. The type III solvated crystalline forms of lopinavir were then isolated by filtration. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Separate X-ray crystallographic parameters and experimental details for Type III ethyl acetate hemisolvated crystalline lopinavir Experimental details Crystal data Crystal system Grid parameters Space group With value Deale Orthorhombic a = 23.961 (9) A b = 27.58 (1) A c = 11.967 (4) A V = 7907 (5) A ³ P2221 (# 20) 1.22 g / cm ³ Intensity measurements Diffractometer Radiation Temperature 20x Correction Number of reflections measured RigakuAFC5R Cu Κα (λ = 1.54178 A) is stable 120.2 ° Lorentz - polarization Absorption (Transmission factors 0.87-1.00) Total: 6520 Unique: 6520 Dissolution of the structure and purification Number of observations (1> 3.0 σ (I)) 2154 Number of variables 443 Reflections / ratio of parameters 4.86 Residues: R; Rw 0.096; 0.093 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · In one example, the Type III desolvated crystalline form of lopinavir is obtained from acetonitrile. From all other solvents it was not possible to obtain a fully desolvated Type III crystalline form of lopinavir. Type III desolvated crystalline forms of lopinavir are useful in the purification and isolation of lopinavir and in the preparation of pharmaceutical preparations for the administration of lopinavir. The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing a Type III desolvated w form of lopinavir and differentiating Type III desolvated crystalline forms of lopinavir from other crystalline forms of lopinavir, with the exception of a Type III solvated crystalline form. The type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of logishavir) also has the characteristic solid phase FT mid-infrared bands shown in Table 3. Table 3 shows the interval of peak positions for each of the 16 characteristic mid-infrared bands. solid phase FT w mid-infrared spectrum of type III desolvated crystalline form lopinavir. This means that the Type III desolvated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in Table 3. Most typical of Type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of lopinavir) are the positions of solid-phase FT mid-infrared bands for amide bonded carbonyl elongation. One strip is located in the interval 1655-1662 cm ⁴ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·················· Type III desolvated crystalline form of lopinavir. Often a second strip appears (in the range 1636-1647 cm &lt; -1 ^&gt; ) as the shoulder of the first strip, or it is not well distinguished from the first strip and is distinguished three times as a second strip. Any type III desolvated crystalline form of lopinavir (including virtually pure Type III desolvated crystalline form of lopinavir) will peak at a position in the range 1655-1662 cm ' ¹ and may also peak at a position in the range 1636-1647 cm' ¹ as a shoulder of peak position in the range 1655-1662 cm ^'1. The solid phase FT medium infrared spectrum of the Type III desolvated crystalline form of lopinavir is shown in FIG. 21. The solid phase FT infrared spectrum in the near region of Type III desolvated crystalline form of lopinavir is shown in FIG. 23. Solid Phase 100 MHz Spectrum ¹³ The nuclear magnetic resonance of the type III desolvated crystalline form of lopinavir is shown in FIG. 24. A DSC thermogram of the type III desolvated crystalline form of lopinavir is shown in FIG. 25. The DSC thermogram of the type III desolvated crystalline form of lopinavir shows a melting endotherm beginning at 95 ° C and a peak W at 98 ° C (ΔΗ = 18 J / g) when performing differential scanning colorimetry at a scan rate of 1 ° C / min up to 150 ° C for the sample, at losses of 0.0% of the original weight of the sample at heating from 1 ° C / min to 150 ° C The positions of the two-theta angles of characteristic peaks in the X-ray powder diffraction profile of Type III desolvated crystalline lopinavir (including virtually pure Type III desolvated crystalline lopinavir) as shown in FIG. 23, ca: 4.85 ° ± 0.1 °, 6.39 ° ± · · · · · · · · · · · · · · · · · · · · · · · 0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 °, and 17.70 ° ± 0.1 °. In particular, Type III desolvated crystalline lopinavir (including virtually pure Type III desolvated crystalline lopinavir) is characterized by peaks in the powder X-ray diffraction profile having the two-theta angles positions shown in FIG. 23: 4.85 ° ± 0.1 °, 6.39 ° ± 0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 °, 17.70 ° ± 0.1 °, 18.70 ° ± 0.1 °, 20.68 ° ± 0.1 °, 20.92 ° ± 0.1 °, 22.06 ° ± 0.1 °, and 22.76 ° ± 0.1 °. Separate X-ray crystallographic parameters and experimental details for Type III desolvated crystalline lopinavir Experimental details Crystal data Crystal system Grid parameters Orthorhombic a = 24.0465 (10) A b = 27.5018 (11) A c = 11.9744 (3) A V = 7918.9 (8) A ³ Space group With value P2221 (# 20) 8 Deale 1,055 g / cm ³ Intensity measurements Diffractometer Radiation Nonius Kappa CCD Mo Κα (λ = 0.71073 A) Temperature room max 61 ° Number of Reflections Measured Total: 28494 Unique: 5148 Dissolution of the structure and purification Number of observations (Ι> 3.0 σ (I)) 4069 Number of variables Reflections / attitude of 442 parameters Residues: R; Rw 9.21 0.056; 0.116 In another method of the present invention, an unsolvated crystalline form of lopinavir is presented. For the purpose of identification, the unsolvated crystalline form of lopinavir of this method is designated Type IV. The type IV unsolvated crystalline form of lopinavir is useful in purifying or isolating lopinavir and in the preparation of pharmaceutical preparations for the administration of lopinavir. In the preferred method of Type IV, the unsolvated crystalline w form of lopinavir is substantially pure compared to other forms of lopinavir, including amorphous, hydrated forms, solvated forms and other unsolvated or desolvated forms. The solid-phase FT mid-infrared spectrum has been found to be a means of characterizing the Type IV unsolvated form of lopinavir and differentiating the Type IV unsolvated crystalline form of lopinavir from other crystalline forms of lopinavir. ·· ···· • ·· • • · • • · • · · • • « • · • • · • · • • · • • • • · · • · • • · • • · • · • · · • · • · • · · · Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) has the characteristic solid phase FT mid-infrared bands shown in Table 4. Table 4 shows the interval of peak positions for each of the 19 characteristic mid-infrared FT bands. medium infrared spectrum of type IV unsolvated crystalline form of lopinavir. This means that the Type IV unsolvated crystalline form of lopinavir will have a peak in position within the interval (minimum to maximum) for each of the peaks shown in Table 4. When the solid-phase mid-infrared spectrum is obtained at a resolution of 4 cm-1, it can to be observed to peak at a position in one or more of the following additional characteristic bands: 1668-1674 cm ^_1 (strong), 1656 to 1662 cm-amplification), 1642-1648 cm ^'1 (strong). At higher resolution or after Fourier transform, these additional peaks are clearly distinguished. Most typical of Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) are the positions of solid-phase FT medium infrared bands for amide bonded carbonyl elongation. These bands are located in the intervals 1680-1685 cm &lt; -1 ^&gt; and 1625-1630 cm &lt; -1 ^&gt; for the type IV unsolvated crystalline form of lopinavir. In addition, especially in high resolution, bands are located in the interval 1668-1674 cm ^'1, 1656-1662 cm' ¹ and 16421648 cm ^'1. Any Type IVI unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) will have a peak at a position in the range 1680-1685 cm ' ¹ and a peak at a position in the range 1625-1630 cm' ¹ and also z ft · »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Thus, there may be a peak in the position in the interval 1668-1674 cm ' ¹ , a peak in the interval 1656-1662 cm ⁴ and a peak in the interval 1642-1648 cm' ¹ . In addition, Type IVI unsolvated crystalline form lopinavir (including substantially purified Type IV unsolvated crystalline form lopinavir) is characterized by solid state IR peak position in any of the intervals: 780-784 cm ^'1, 764-768 cm' ¹ and 745 -749 cm ¹ . Table 4 Peak position intervals for solid phase strips FT medium infrared bands for Type IV unsolvated crystalline form of lopinavir Minimum cm ' ¹ Maximum cm ' ¹ Intensity * 3433 3439 In 3415 3421 In 3406 3412 In 3338 3345 ss Chin- 3309 3315 In 3272 3278 In 3082 3089 Sl 3025 3030 Sl 2959 2965 In 2926 2932 Sl 2870 2875 Sl 1680 1685 p 1625 1630 MS 1514 1526 p 1451 · · · · · · · · · · · · · · · · · · · · * · · · · · · • · · · · · · · · · · · · · · 4 · · · <· · · · 1456 SS 1306 1312 In 1189 1194 In 1089 1094 Sl 1044 1050 Sl * Cl = weak; B = moderate; CC = medium strong; C = strong; MS = very strong Type IV unsolvated crystalline form of lopinavir has a solid-phase FT mid-infrared spectrum, a solid-phase FT ^W infrared spectrum in the near region, a powder X-ray diffraction pattern, a solid-phase 100 MHz spectrum ¹³ C nuclear magnetic resonance imaging (DSC), and a differential LC are shown in FIGS. 26, 27, 28, 29 and 30 respectively. The positions of the two-theta angles of the characteristic peaks in the powder X-ray diffraction profile of type IV unsolvated crystalline lopinavir (including virtually pure Type IV unsolvated crystalline form V lopinavir) as shown in FIG. 28, ca: 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 ° and 18.53 ° ± 0.1 °. In particular, Type IV unsolvated crystalline form of lopinavir (including virtually pure Type IV unsolvated crystalline form of lopinavir) is characterized by peaks in the powder X-ray diffraction profile having the positions of the two-theta angles shown in FIG. 28: 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 10.80 ° ± 0.1 °, 12.04 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 4 « 4444 4 • 4 • 4 · • • • • 4 · 4 • · • · • 4 • • 4 • • · • • • • • • 4 • · • • e • • · • · • is 4 4 4 • · 4444 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.26 ° ± 0.1 °, 18.53 ° ± 0.1 °, 20.47 ° ± 0.1 ° and 25.35 ° ± 0.1 °. The DSC thermogram of the Type IV unsolvated crystalline form of lopinavir shows a melting endotherm beginning at 117 ° C and a peak at 122 ° C (ΔΗ = 47 J / g) when performing differential scanning colorimetry at a scan rate of 1 ° C / min to 150 ° C. The individual parameters for X-ray crystallography and the experimental details for Type IV unsolvated crystalline form of lopinavir are as follows: Separate X-ray crystallographic parameters and experimental details for Type IV unsolvated crystalline lopinavir Experimental details Crystal data Crystal system Grid parameters Space group With value Deale Orthorhombic a = 15.065 (8) A b = 25.27 (1) A c = 9.732 (3) A V = 3704 (3) A ³ P2! 2i2i (# 20) 4 1.13 g / cm ³ Intensity measurements Diffractometer Radiation Temperature Rigaku AFC5R Cu Κα (λ = 1.54178 A) is stable • • • · • • ···· • • • ·· · • · • · • • * ·· • · • • • • • • • • • • · • · • • • • ·· • · ··· ·· ·· ···· 120.21 ° 2Θ max Correction Lorentz - polarization Absorption (Transmission factors: 0.8362-09496) Number of Reflections Measured Total: 3145 Dissolution of the structure and purification Number of observations (Ι> 3.0 σ (I)) 1434 Number of variables 415 Reflections / ratio of parameters 3.46 Residues: R; Rw 0.081; 0.085 Type IV unsolvated crystalline form of lopinavir can be obtained from acetonitrile by slow cooling and slow ignition of a saturated solution or exposure of amorphous lopinavir to an atmosphere of acetonitrile. In addition, Type IV unsolvated lopinavir crystals may be added to the solution of lopinavir in acetonitrile to induce crystallization to give Type IV unsolvated lopinavir crystals. The following examples can be used to further illustrate the method of the present invention for the preparation of new crystalline forms of lopinavir. Example 1 Preparation of Type I highly hydrated crystalline form of lopinavir A saturated solution of lopinavir in a mixture of 20 mL ethanol and 40 mL water was prepared at room temperature. The saturated solution was stirred at room temperature and water (54 mL) was slowly added using a syringe pump at a feed rate of 0.15 mL / min. Stirring overnight gave a precipitate (crystals) which was filtered. Example 2 Preparation of Type I highly hydrated crystalline form of lopinavir The NMR tube was filled with 1.75 mL of water. Subsequently, 0.5 mL of lopinavir solution in ethanol (99.482 mg / mL ethanol) was applied very carefully to the water layer. The tube was closed to prevent evaporation and was left unshaken. After about 30 days, crystals of type I hydrogenated crystalline form of lopinavir containing more than 0.5 molecules of water per molecule of lopinavir were obtained. Example 3 Preparation of Type I highly hydrated crystalline form of lopinavir Lopinavir (30 g) was dissolved in a mixture of 360 mL of deionized distilled water and 418 mL of ethanol 190 proof by heating with moderate stirring at about 60 ° C. The hot solution was filtered gravitationally to remove · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· undissolved material. The filtrate was slowly cooled with gentle stirring to room temperature at which point it was seeded with embryos of about 50 mg of the product of Example 1. The mixture was stirred at a moderate rate at room temperature for three days. The resulting mixture was filtered under vacuum. The filtered solid was transferred onto filter paper and all lumps were broken by gentle spatula manipulation. The solid was then transferred to a glass crystallization dish and placed in a desiccator over saturated sodium chloride solution to maintain a constant relative humidity of 75%. After drying for 12 days at room temperature (24 ± 1 ° C) and a relative humidity of 75%, about 20.5 g of the desired hydrate form of lopinavir was obtained. X-ray diffraction profile of a powder sample (FIG. 5). ¹³ C NMR spectrum of a solid at 100 MHz (FIG. 6). Solid phase FT in the near infrared region (FIG. 7). Solid phase FT in the mid-infrared region (FIG. 8). The product contained 4.3% volatile material according to thermo-gravimetric analysis. Example 4 Obtaining a Type ϊ hydrated crystalline form of lopinavir containing about 0.5 molecules of water per molecule of lopinavir The product of Example 3 (about 100 mg) was placed in an X-ray powder diffractometer holder, complete with a chamber for controlled sample atmosphere and heating. The sample was heated at HS / min to 30 ° C in · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Атмос атмос су су на атмос атмос. The conversion to the hemihydrate was performed for 60-90 min. Powder X-ray diffraction profile (FIG. 1) · Example 5 Preparation of Type I Hydrated Crystalline Form of lopinavir containing about 0.5 molecules of water per molecule of lopinavir The product of Example 3 (1 g) was dispersed as a thin layer in a polypropylene weight canister and dried overnight in a vacuum oven at - 65 kPa and ambient temperature. The resulting hygroscopic product (lopinavir hemihydrate) was transferred into glass ampoules and dried again for 6 hours at about - 65 kPa and ambient temperature. The ampoules were then quickly sealed with polypropylene lids and stored in a desiccator over anhydrous calcium sulfate. ¹³ C NMR spectrum of a solid at 100 MHz (FIG. 2). Solid phase FT in the near infrared region (FIG. 3). Solid phase FT in the mid-infrared region (FIG. 4). The product contained 2% volatile material as determined by thermo-gravimetric analysis. Example 6 Preparation of Type II isopropanol semisolvated crystalline form of lopinavir Lopinavir (16 g) was dissolved in 50 mL of isopropanol by heating the mixture on a hot plate to boiling point with magnetic stirring. The solution was then cooled to room temperature 4 · · · · · · · · · · · · · · · · · · · · · · · · · · 4 · · · · · · · · · · · · · · · · · · · · · · и и и и и и и и и и и и и и и и и и и и и и и и и и температура температура температура и температура и температура температура температура и температура и температура температура температура температура температура температура температура The resulting mixture was stirred at room temperature for 24 hours with stirring sufficient to maintain the precipitate in suspension. The precipitate was collected by suction filtration and air-dried to give 9.9 g of Type II isopropanol semisolvate crystalline form of lopinavir. The thermogravimetry of the product indicated the presence of a volatile material corresponding to 1 mole of isopropanol for every two mole of lopinavir. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvate crystalline form of lopinavir Type II. Solid-phase FT in the mid-infrared region (FIG. 9). Solid phase FT in the near infrared region (FIG. 14). Example 7 Preparation of Type II isopropanol solvate crystalline form of lopinavir (1.6% isopropanol by weight according to thermogravimetry) Lopinavir (1 g) was suspended in 2.5 mL isopropanol in a glass ampoule containing four 4 mm diameter glass beads to improve stirring. The ampoule was closed with a lid and the suspension rotated in a drum at room temperature for 4 months. The suspension was then transferred to a Petri dish and the solvent was allowed to evaporate slowly. The Petri dish was then placed in a vacuum oven which was heated to 50 ° C and the sample was dried at -65 kPa at 50 ° C for 25 days to give the title compound. The product contained 1.6% volatile material according to thermogravimetry. Example 8 Preparation of Type II isopropanol solvate crystalline form of lopinavir (2% isopropanol by weight according to thermogravimetry) A sample of the product of Example 6 was washed with heptane, then dried for two days in a rotary evaporator. The residue was taken up in a Petri dish and dried in a vacuum oven, which was then heated to 50 ° C and the sample was dried at -65kPa at 50 ° C for 3 days to obtain the title compound. The product contained 2% volatile material according to thermogravimetry. Solid phase FT in the mid-infrared region (FIG. 10). Solid phase FT in the near infrared region (FIG. 15). Example 9 Preparation of Type II ethyl acetate hemisolvate crystalline form of lopinavir Example 9A Preparation of crude lopinavir Crude lopinavir prepared according to U.S. Patent No. 5,914,332 (Example 38) from (2S, 3S, 5S) -2-aminoH3-3-fluoro-CH-5- [2S- (1-tetrahydropyrimid-2-one) -3-methylbutanoyl] amino- The 1,6-diphenylhexane (S) -pyroglutamic acid salt (about 85 g, corrected for solvent content) was dissolved in 318.5 grams of ethyl acetate and the solution was concentrated to an oil in vacuo. The residue was dissolved in 225 grams of ethyl acetate, then concentrated twice to an oil in vacuo. The residue was dissolved in ethyl acetate (approximately 300 mL) at 65 ° C, filtered to remove any trace of undissolved solids and concentrated to a foam in vacuo. The foam was dissolved in 338 grams of ethyl acetate and this solution was divided into four equal portions. Example 9 B. C Obtaining Type II ethyl acetate hemisolvate crystalline form of lopinavir Part of the lopinavir solution obtained in Example 9A was concentrated to an oil in vacuo, then dissolved in 50 mL absolute ethanol. The solvent was removed in vacuo. The residue was kept under vacuum with heating (approximately 5560 ° C) for an additional 30 minutes. The resulting foam was dissolved in ethyl acetate (87 mL) at room temperature. In less than five minutes of stirring, the solid phase was apparent. The resulting slurry was stirred for 16 hours, then diluted with 87 mL of heptanes. After three hours, solids were collected by filtration, washed with 36 mL of EtOAc / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 19.4 g of Type II ethyl acetate hemisolvate of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 11). Solid phase FT in the near infrared region (FIG. 16). The product contained 4.4% volatile material according to thermogravimetry. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Example 9 B. Alternative preparation of Type II ethyl acetate hemisolvate crystalline form of lopinavir Crude lopinavir prepared according to U.S. Patent No. 5,914,332 (Example 38) from (2S, 3S, 5S) -2-aminoHCO-3-benzylCH-5- [2S- (tetrahydropyrimid-2-one) -3-methyl butanoyl] amino The 1,6-diphenylhexane (s) pyroglutamic acid salt (about 20 g, corrected for solvent content) was dissolved in 118 grams of ethyl acetate and then concentrated to an oil in vacuo. The residue was dissolved in 95.7 grams of ethyl acetate at 46 ° C, then concentrated to an oil in vacuo. The residue was dissolved in 95.8 grams of ethyl acetate at 64 ° C. Karl Fischer moisture measurements showed less than 0.05% water. The product solution was cooled to 41 ° C and seeded with 0.20 g of the product of Example 9B. The solution was cooled to 35 ° C and stirred at this temperature for 1.25 hours. The resulting slurry was then cooled to 15 ° C for more than 10 minutes and stirred at 15-18 ° C for 1.5 hours. The solids were collected by filtration, washed with 13.3 grams of ethyl acetate and dried under vacuum at 56-58 ° C for 16 hours, yielding 12.3 g of Type II ethyl acetate hemisolvate of lopinavir. Example 10A Preparation of Type II ethyl acetate semi-solvate crystalline form of lopinavir (having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir according to thermogravimetry) Part of the lopinavir solution obtained in Example 9A was concentrated to an oil in vacuo, then dissolved in 50 mL absolute ethanol. The solvent was removed in vacuo. The residue was kept under vacuum with heating (approximately 5560 ° C) for an additional 30 minutes. Crystalline embryos from the product of Example 9B were added to the foam obtained. The foam residue was dissolved in ethyl acetate (87 mL) at ambient temperature. In less than five minutes of stirring, the solid phase was apparent. The resulting slurry was stirred for 16 hours, then diluted with 87 mL of heptanes. After three hours, solids were collected by filtration, washed with 36 mL EtOAc / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 19.37 g of Type II ethyl acetate solvate of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 12). Solid phase FT in the near infrared region (FIG. 17). The product contained 1.7% volatile material according to thermogravimetry. Example 10B Alternative preparation of Type II-ethyl acetate solvate crystalline form of lopinavir (having less than 0.5 mol of ethyl acetate per 2 mol of lopinavir according to thermogravimetry) Crude lopinavir solution prepared according to U.S. Patent No. 5,914,332 (Example 2; coupling 17.0 g of (2S, 3S, 5S) -2 (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6diphenylhexane with 8.0 g of 28- (1-tetrahydropyrimid-2-one) -3methylbutanoic acid via EDAC / HOBT coupling) in isopropyl acetate (about 250mL) was concentrated to an oil in vacuo. The residue was dissolved in 250 mL of ethyl acetate and concentrated to a foam in vacuo. The foam was dissolved in 120 ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ML warm ethyl acetate. The solution was divided into three equal portions of 44.9 grams each. The solutions were cooled to room temperature and crystallization rapidly followed. One of these parts was stirred at room temperature overnight. The solids were collected by filtration, washed with 8 mL of ethyl acetate, then dried under vacuum at 22 ° C for 40 hours, then further dried for 44 hours under vacuum at 70 ° C to give 6.23 grams of Type II ethyl acetate solvate. lopinavir. Example 11 Preparation of Type II hemisolvate crystalline form of lopinavir with chloroform Lopinavir (10 g) was dissolved in 30 mL of chloroform. The solution was then heated to reflux on a hot magnetic stirring plate. After reducing the volume of the solution to about 1/2 of the initial volume, about 10 mL of n-heptane was added dropwise until the solution began to cloud. An additional 30 mL of chloroform was then added and the boiling continued until the volume was again about 1/2 of the initial volume. About 20 mL of chloroform was then added and the boiling continued until the volume was again about 1/2 of the initial volume. The mixture was then cooled slowly to room temperature and allowed to partially evaporate. After slow evaporation, a glassy residue with molasses consistency remains. This substance was mixed with about 20 mL of chloroform and heated on a hot plate. Then n-heptane was added dropwise until a precipitate formed. The precipitate was dissolved by reheating the mixture. The warm solution was transferred to a beaker, which was placed inside a jar containing about 20 mL of heptane and allowed to cool. After about 1 hour a thick solid precipitate formed. Most of the precipitate was redissolved by adding about 20 mL of chloroform to the contents of the beaker. After allowing this mixture to stand for about 1 hour, little needle-shaped crystals form. More heptane (about 40 mL) was added to the beaker containing the beaker and the jar was closed and left to stand. After a day, the beaker contained a large number of crystals. The crystals were collected by vacuum filtration. The crystalline mass was crushed carefully using a spatula and the crystals were washed with chloroform / heptane from the bank outside the beaker in which the crystals were grown. Thermogravimetry of the product indicates the presence of a volatile material corresponding to 1 mole of chloroform for every two mole of lopinavir. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvate crystalline form of lopinavir Type II. Solid phase FT in the mid-infrared region (FIG. 13). Solid phase FT in the near infrared region (FIG. 18). Example 12 Preparation of Type III ethyl acetate solvated crystalline form of lopinavir Lopinavir (7.03 g) was dissolved in ethyl acetate (33.11 g) at 71 ° C. The solution was cooled to 42 ° C for 45 minutes, with solids apparent. The sludge was cooled to 35 ° C for 30 minutes, then stirred for one hour. The slurry was then cooled to 15 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ ·· for 13 minutes and then stirred for one hour. Mixed heptanes (25.1 g) were added dropwise over 13 minutes. The resulting slurry was stirred for 30 minutes. The solids obtained were collected by filtration, washed with ethyl acetate / mixed heptanes (1: 1 v / v, 20 mL) and dried in vacuo at 62 ° C for 20 hours, yielding 6.4 g of the compound from the title. X-ray powder diffraction analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was Type III solvated crystalline form of lopinavir. Solid-phase FT in the mid-infrared region (FIG. 19). Solid phase FT in the near infrared region (FIG. 20). The product contains 2.3% volatile material according to thermogravimetry. Example 13 Preparation of Type III ethyl acetate solvated crystalline form of lopinavir Approximately 100 mg of lopinavir was dissolved in about 3 mL of ethyl acetate. About 3 mL of heptane was slowly and carefully added to this solution. After standing, crystals of type III solvated crystalline form of lopinavir by liquid diffusion crystallization. Example 14 Preparation of Type III ethyl acetate solvated crystalline form of lopinavir One portion of the lopinavir solution prepared in Example 9A was diluted with 14.8 grams of ethyl acetate and heated to 70-75 ° C, ··················································· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 75 grams of heptanes, maintaining an internal temperature higher than 70 ° C. The resulting solution was heated to 7 5 ° C for 15 minutes, then allowed to gradually cool to room temperature. After stirring overnight at room temperature, the solids were collected by filtration, washed with 36 mL of ethyl acetate / heptanes (1: 1 v / v) and dried in vacuo at 60 ° C for 72 hours, yielding 21.5 grams of the compound of the title. W Example 15 Preparation of Type III desolvated crystalline form of lopinavir Lopinavir (5 g) was placed in a 100 mL beaker. Acetonitrile was added in such a way that approximately 95% of lopinavir was dissolved. Some needle-shaped crystals remain undissolved. The beaker was placed inside a jar containing about 1 cm thick layer of anhydrous calcium sulphate (DRIERITE). The jar was closed and the material was left alone at room temperature. After staying overnight, a large amount of white crystalline material precipitated. The supernatant (about 6 mL) was decanted from the beaker. Fresh acetonitrile (3-4 mL) was added to the precipitate, which was then carefully ground with a spatula. The solid was collected by suction filtration and washed with about 1 mL of acetonitrile. The solid was transferred to a Petri dish and dried in vacuo at room temperature to obtain the Type III desolvated crystalline form of lopinavir. The product contained less than 0.05% ······ · ·· 9 ·· • · 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 99 99 99 999 99 99 9999 volatile material according to thermogravimetry. Solid-phase FT in the mid-infrared region (FIG. 21). Solid phase FT in the near infrared region (FIG. 22). X-ray diffraction profile of the powder sample (FIG. 23). ¹³ C NMR spectrum of the solid at 100 MHz (FIG. 24). DSC thermogram (FIG. 25). Example 16 Preparation of Type IV unsolvated crystalline form of lopinavir Lopinavir (amorphous, 1 g) was placed in a crystallization dish (A). This dish was placed in a larger crystallization dish (B) containing about 10 mL of acetonitrile and placed on a hot plate. Medium size crystallization dish (B) was reversed and placed above plate A, but inside plate B. A wide crystallization plate (D) was reversed and placed above plates A, B and C. The hot plate was warmed to about 35 °. C and then the hotplate was removed. The whole structure was then left to stand at room temperature for 10 days. After 10 days, all the acetonitrile was evaporated. A portion of the crystalline product obtained (0.1 g) was mixed with acetonitrile (0.6 mL) and stirred for 1 hour. The mixture was filtered and the solid allowed to air to dry, yielding a Type IV unsolvated crystalline form of lopinavir. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Example 17 Preparation of Type IV unsolvated crystalline form of lopinavir Lopinavir (259 g) was dissolved in 500 g of acetonitrile at 40-42 ° C. The cloudy solution was filtered through a 0.45 μ nylon membrane bottomed flask of 2 L, and to the solution were added a few crystals of the product of Example 16. The flask was placed on a rotary evaporator at 10-20 rpm ¹ overnight without heating and vacuum . As a result, a dense suspension of needle-like crystals is obtained. The slurry was cooled in an ice bath for 1 hour and then filtered on a desktop night filter in a nitrogen atmosphere and covered with nylon. The filter cake was washed with acetonitrile and dried to dryness under nitrogen for 30 minutes. The precipitate was then transferred to a crystallization vessel and dried for two days at 60-65 ° C at 20-21 "Hg in a nitrogen atmosphere, yielding 194.3 g of Type IV unsolvated crystalline form of lopinavir. The product was subjected to X-ray crystallographic diffractometry and was classified as Type IV unsolvated crystalline form of lopinavir by solid-state FT medium infrared spectroscopy (FIG. 26), solid-phase FT near-infrared spectra (FIG. 27), beams (FIG. 28), solid phase ¹³ C MHz at 100 MHz (FIG. 29) and DSC thermogram (FIG. 30) The product contains less than 0.1% volatile material determined by thermal gravimetric analysis. When taken for the treatment of an illness caused by the AIDS virus, lopinavir is preferably used in ·· ···· • • • ·· · • ·· « • • • · • · • · • · • e • • • • • • · • · • · • ·· ··· is · • · ···· 4: 1 combination with ritonavir (lopinavir: ritonavir). A preferred pharmaceutical preparation for the administration of lopinavir comprising a 4: 1 ratio of lopinavir: ritonavir has the following composition and is encapsulated in soft elastic gelatin capsules. Lopinavir 133.3 mg Ritonavir Oleic acid, NF 33.3 mg 598.6 mg Propyl glycol, United States Pharmacopoeia Polyoxyl 35 castor oil, NF (Cremephor EL®) Purified Water, US Pharmacopoeia (distilled) 64.1 mg 21.4 mg 4.3 mg If a hydrated or solvated crystalline form of lopinavir is used in the preparation, the amount of hydrated or solvated crystalline form of lopinavir is recalculated to take into account the amount of water or other solvent present in the crystalline form. A preferred formulation can be prepared according to the following method. The following protocol is used to obtain 1000 soft gelatin capsules: Scale (mg / capsule) Name Quantity (g) Q.S. Nitrogen, N.F. Q.S. 578.6 Oleic acid, N.F. 578.6 33.3 Ritonavir 33.3 64.1 Propylene glycol, Pharmacopoeia of 64.1 USA · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 4.3 Water, purified, Pharmacopoeia of USA (Distilled) 4.3 133.3 Lopinavir 133.3 10.0 Oleic acid, N.F. 10.0 21.4 Polyoxyl 35 castor oil, NF 21.4 10.0 Oleic acid, N.F. 10.0 The mixing vessel and the appropriate container are purged with nitrogen. The mixer was charged with 578.6 g of oleic acid. The mixer is J heated to 28 ° C (not exceeding 31 ° C) and stirring begins 33.3 g of ritonavir were then added to the oleic acid with continuous stirring. Propylene glycol and water are then added to the mixer and stirring is continued until the solution is clarified. 133.3 g of lopinavir are then added to the mixer and stirring is continued. Then 10 g of oleic acid are added to the mixer and stirring is continued until a clear solution is obtained. 21.4 g · were then added to the mixer; polyoxyl 35 castor oil NF, after stirring 10 g 1 oleic acid. The solution is stored at 2 - 8 ° C 4 sec I until encapsulation of the mixture. 0.855 g of solution are placed in each soft gelatin capsule and then the soft gelatin capsules are dried and stored at 2-8 ° C. As used herein, the term "substantially pure" when used with respect to the crystalline form of lopinavir, refers to the crystalline form of lopinavir having more than 90% purity. This means that the crystalline form of lopinavir does not contain more than about 10% of another compound and, in particular, does not contain more than about 10% of any other ····· · ·········· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Lopinavir form such as amorphous lopinavir, solvated form, unsolvated form and desolvated form. In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 95% pure. This means that the crystalline form of lopinavir contains no more than about 5% of another compound and, in particular, does not contain more than about 5% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms. In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 97% pure. This means that the crystalline form of 'lopinavir does not contain more than about 3% of another compound and, in particular, does not contain more than about 3% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms . In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 98% pure. This means that the crystalline form of lopinavir contains no more than about 2% of another compound and, in particular, does not contain more than about 2% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms. In particular, the term "substantially pure" refers to the crystalline form of lopinavir, which is more than 99% pure. This means that the crystalline form of lopinavir contains no more than about 1% of another compound and, in particular, does not contain more than about 1% of any other form of lopinavir such as amorphous lopinavir, solvated form, unsolvated form and desolvated forms. • · Powder X-ray diffraction analysis was performed as follows. X-ray diffraction samples were prepared by spreading a powdered substance (powdered fine powder in a pestle mortar or glass microscope slides for a limited amount) into a thin layer on a sample support and gently pressing the sample microscopically. Samples were analyzed in one of three configurations: a circular bulk pad, a quartz plaque for the control zero, or a hot plate (similar to the placement of the control plate). X-ray diffraction was performed using an XDS 2000 ΘΙΘ diffractometer (Scintag; 2 kW normal-focus X-ray tube with liquid nitrogen or Peltier cooled solid phase detector; 45 kV and 30 - 40th, X-ray source: Cu-Kal: X-ray source: Cu) ; range: 2.00-40.00 ° two theta; scan rate: 0.5 or 2 degrees / minute), XRD-6000 diffractometer (Schimadzu, fine-focus X-ray tube with Nal scintillation detector, 40-45 kV and 30-40th, source X-rays: CuKal; Range: 2.00-40.00 ° two theta; Scanning speed: 0.5 or 2 degrees / minute) or 1-2 X-ray diffraction odometer (Nicolet; scintillation detector; 50 kV and 30 ta, X-ray source: Cu-Kal; range: 2.00-40.00 ° two theta; scan rate: 0.5 or 2 degrees / minute). The relative humidity of the sample in the hot plate can be controlled using a relative humidity generator (model RH 200, VTI Corp.). The positions of the peaks of the characteristic X-ray diffraction profile are reported for polymorphs with respect to the positions of the angles (two theta) with a tolerable variability of ± OG. Allowable variability is determined by the Pharmacopoeia of · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · United States, pp. 1843-1844 (1995). A ± 0.1 ° variability is used when comparing two powder diffraction profiles. In practice, if the profile of the diffraction peak of one profile falls within the interval of angular positions (two theta), which is the measured peak position ± 0.1 ° and the peak of the diffraction profile of the print profile falls within the interval of angular positions (two theta), which is the measured peak position ± 0.1 ° and if these intervals of peak positions overlap, then the two peaks are considered to have identical angular positions (two theta). d For example, if a diffraction profile peak from one profile is determined to have a peak position of 5.20 ° for comparability, the allowable variability allows a peak to be set in the range 5.10 - 5.30 °. If a peak position of 5.35 ° is set for the comparative peak from the other diffraction profile, for the sake of comparability, the allowable variability allows the peak to be set in the range 5.25 - 5.45 °. Since there is an overlap between the two intervals of the peak positions (ie 5.10 ° - 5.30 ° and 5.25 ° - 5.45 °), the two peaks that are compared can be considered as having the same angular position (two theta) . έ ^{w The} solid-state nuclear magnetic resonance analysis of the samples was performed as follows. An apparatus was used Bruker AMX-400 with the following parameters: CP-MAS (cross polarized magnetic angular rotation); the frequency of the ¹³ C spectrometer was 100.6 MHz; pulse sequence - VA-CP2LEV; contact time was 2.5 milliseconds; rotation speed - 700 Hz; recycling delay time of 5.0 sec .; 3000 scans). The FT near-infrared sample analysis was performed as follows. Samples were analyzed as undiluted powdered substances contained in a transparent glass vial. It was used Nicolet Magna System 750 FT-IR spectrometer c handler Nicolet SablR c fiberoptic probe c diffuse reflectance in the near infrared region with the following parameters: detector PbS, prism CaF2, number of scans of sample - 16, resolution 8 cm ^'1. The FT average infrared analysis of the samples was performed as follows. Samples were analyzed as undiluted powders. A Nicolet Magna System 750 FT-IR spectrometer with a Nicolet NIC-PLAN microscope with a MCT-A detector with liquid nitrogen cooling was used. The samples were placed in a 13 mm x 1 mm BaF2 sample disk mount. 64 scans were carried out at a resolution of 4 cm ' ¹ . The differential scanning calorimetric analysis of the samples was performed as follows. A Differential Scanning Calorimetry Model 2920 AT.A Instruments with DSC Cell, TA Instrument with Thermal Solution Data Analysis Software, Version 2.3 was used. The analysis parameters are: Sample size: 4-10 mg, placed in an aluminum vial sealed with a needle lid, heating rate: 1 ° C / min in a nitrogen atmosphere (40 - 50 mL / min). Thermal gravimetric analysis was performed by heating the sample from room temperature to 200 ° C at a heating rate of 1 ° C or 5 ° C / minute. The above examples illustrate the invention without limiting the invention to the examples described. Variations and changes that are apparent to anyone experienced in the prior art fall within the scope and nature of the present invention, which is defined by the following claims. Patent Claims 1. Crystalline hydrated form of lopinavir. 2. A crystalline form of lopinavir according to Claim 1 with a peak in the solid state infra-red spectrum at a position in the range of 1652 to 1666 cm ^'1 and a peak in the solid state infra-red spectrum at a position in the range of 1606 to 1615 cm' ^1. 3. Actually pure crystalline hydrated form of lopinavir. 4. A crystalline form of lopinavir according to claim 3, with a peak in the solid state infra-red spectrum at a position in the range of 1652 to 1666 cm ^'1 and a peak in the solid state infra-red spectrum at a position in the range of 1606 to 1615 cm' ^1. 5. solvated crystalline form of lopinavir with a peak in the solid state infra-red spectrum at a position in the range of 1661 to 1673 cm ^-1, a peak in the solid state infra-red spectrum at a position in the range of 1645 to 1653 cm ^'1 and a peak in the solid state infra-red spectrum as a position in the range 1619- 1629 cm ¹ . 6. In fact, pure solvated crystalline form of lopinavir with a peak in the solid state infra-red spectrum at a position in the range of 1661 to 1673 cm ^'1 peak in the solid state infra-red spectrum at a position in the range of 1645 to 1653 cm' ¹ and a peak in the solid state infra-red spectrum in the position in interval 1619 - 1629 cm ' ¹ . • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 7. Crystalline form of lopinavir with a peak in the solid phase infrared spectrum at a position in the range 1655 - 1662 cm &lt; -1 ^&gt; . 8. A crystalline form of lopinavir with a peak in the solid state infra-red spectrum at a position in the range of 1655 to 1662 cm ^'1 and a peak in the solid state infra-red spectrum at a position in the range of 1636 to 1647 cm' ^1. 9. Actually pure crystalline form of lopinavir with a peak in the solid phase infrared spectrum at a position in the range 1655 - 1662 cm &lt; -1 ^&gt; . 10. Actually pure crystalline form of lopinavir with a peak in the solid phase infrared spectrum at a position in the range 1655 - 1662 cm &lt; ^{1 &gt;} and a peak in a solid phase infrared spectrum at a position in the range 1636 - 1647 cm &lt; -1 ^&gt; . 11. Solvated crystalline form of lopinavir with a peak in the solid-phase infrared spectrum at a position in the range 1655 - 1662 cm ¹ . 12. solvated crystalline form of lopinavir with a peak in the solid state infra-red spectrum at a position in the range of 1655 to 1662 cm ^'1 and a peak in the solid state infra-red spectrum at a position in the range of 1636 to 1647 cm' ^1. 13. Actually pure solvated crystalline form of lopinavir with a peak in the solid phase infrared spectrum at a position in the range 1655 - 1662 cm &lt; -1 ^&gt; . 14. In fact, pure solvated crystalline form of lopinavir with a peak in the solid state infra-red spectrum at a position in the range of 1655 to 1662 cm ^'1 and a peak in the solid state infra-red spectrum at a position in the range of 1636 to 1647 cm' ^1. 15. Unsolvated crystalline form of lopinavir. The crystalline form of lopinavir according to claim 15 having a peak in the solid phase infrared spectrum at a position in the range 1680 - 1685 cm &lt; ^{1 &gt;} and a peak in the solid phase infrared spectrum at a position in the range 1625 - 1630 cm &lt; -1 ^&gt; . 17. The crystalline form of lopinavir according to claim 15 with characteristic peaks of powder X-ray diffraction with two theta values of 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ± 0.1 ° and 18.53 ° ± 0.1 °. 18. The crystalline form of lopinavir according to claim 15 with characteristic peaks of powder X-ray diffraction with two theta values of 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 10.80 ° ± 0.1 °, 12.04 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.26 ° ± 0.1 °, 18.53 ° ± 0.1 °, 20.47 ° ± 0.1 °, and 25.35 ° ± 0.1 °. 19. Actually pure unsolvated crystalline form of lopinavir. 20. The crystalline form of lopinavir according to claim 19 having a peak in the solid phase infrared spectrum at a position in the range 1680 - 1685 cm &lt; ^{1 &gt;} and a peak in the solid phase infrared spectrum at a position in the range 1625 - 1630 cm-1. 21. The crystalline form of lopinavir according to claim 19 having a peak in the solid phase infrared spectrum at a position in the range 1680 - 1685 cm &lt; ¹ & gt ^; and a peak in the solid phase infrared spectrum at a position in the range 1668 - 1674 cm &lt; ^{1 &gt;} , and a peak in the solid phase infrared spectrum at the position • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·········· in the range 1656 - 1662 cm ' ¹ , and a peak in the solid phase infrared spectrum at a position in the range 1642 - 1648 cm' ¹ , and a peak in the solid phase infrared spectrum at a position in the range 1625 - 1630 cm ' ¹ . 22. The crystalline form of lopinavir according to claim 19 having characteristic peaks of powder X-ray diffraction with two theta values of 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ± 0.1 ° and 18.53 ° ± 0.1 °. 23. The crystalline form of lopinavir according to claim 19, having characteristic peaks of powder X-ray diffraction profile with values of two theta of 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 10.80 ° ± 0.1 °, 12.04 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.26 ° ± 0.1 °, 18.53 ° ± 0.1 °, 20.47 ° ± 0.1 °, and 25.35 ° ± 0.1 °.