SK14832002A3 - Crystalline pharmaceutical - Google Patents

Abstract

New crystalline forms of lopinavir are disclosed.

Description

Technical field l

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

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) protease inhibitors have proven useful in the treatment of HIV infection after several years of use. A particularly potent and currently proven HIV protease inhibitor is (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- [2- (1-tetrahydropyrimid-2-onyl) -3- methylbutanoyl] amino-1,6-diphenylhexane (also known as lopinavir).

lopinavir

Lopinavir is known to be useful in inhibiting HIV protease and inhibiting HIV infection. Lopinavir is particularly effective in protease inhibition and inhibition

HIV infection when co-administered with ritonavir. When lopinavir is combined with ritonavir, it is particularly effective for inhibiting HIV infection when used in combination with one or more reverse transcriptase inhibitors and / or one or more other HIV protease inhibitors.

Lopinavir and methods for its preparation are disclosed in U.S. Pat. No. 5,914,332, issued June 22, 1999; U.S. Pat. No. 08 / 966,495, filed Nov. 7, 1997; in U.S. provisional patent application no. 60 / 177,020, filed Jan. 19, 2000, and U.S. Pat. No. 09 / 487,739, filed January 19, 2000, all of which are incorporated herein by reference.

It has now unexpectedly been found that lopinavir can be prepared and isolated as such in a family of crystalline forms.

SUMMARY OF THE INVENTION

According to the present invention, there exist new crystalline forms of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5- [2- (1-tetrahydropyrimimid-2-onyl) -3-methylbutanoyl amino-1,6-diphenylhexane (lopinavir).

In one embodiment of the present invention, the crystalline forms of lopinavir are hydrated. For identification, hydrated crystalline forms are referred to as Type I. Hydrated crystalline forms of lopinavir type I contain from about 0.5 molecules of water per lopinavir molecule to about 2 molecules of water per lopinavir molecule.

Hydrated crystalline forms of lopinavir type I are useful in refining or isolating lopinavir during the final steps of the lopinavir preparation process and in preparing pharmaceutical compositions for administration of lopinavir.

The hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule is hygroscopic. Therefore, when maintained under conditions of about 0% relative humidity, type I hydrated crystalline form of lopinavir contains more than 0.5 molecules of water per lopinavir molecule. When the hydrated crystalline form of lopinavir type I is dehydrated to below about 0.5 molecules of water per lopinavir molecule, lopinavir amorphous is obtained.

While crystalline forms of lopinavir type I, containing 0.5 molecules of water per lopinavir molecule and about 2 molecules of water per lopinavir molecule, represent the lower and upper water solvation ranges, respectively, observed for hydrated crystalline forms of lopinavir type I, the water content of the crystalline form may vary depending on the temperature and water content around the crystalline form. The term hydrated type I crystalline form will be used herein in relation to hydrated crystalline forms of lopinavir type I containing from more than 0.5 molecules of water per lopinavir molecule to up to about 2 molecules of water per lopinavir molecule. The above hydrated type I crystalline form suitably contains from about 0.75 to about 1.9 molecules of water per lopinavir molecule. Most preferably, the above hydrated type I crystalline form comprises from about 1.0 to about 1.8 molecules of water per molecule of lopinavir.

In a preferred embodiment, the hydrated crystalline forms of lopinavir type I are substantially pure relative to other forms of lopinavir, including amorphous, solvated, unsolvated and desolvated forms.

The FT spectrum of the solid state infrared region has been found to be a means of characterizing hydrated crystalline forms of lopinavir type I and distinguishing hydrated crystalline forms from other crystalline forms of lopinavir.

Hydrated crystalline forms of lopinavir type I (including substantially pure hydrated crystalline forms of lopinavir type I) have, in the solid state, the characteristic absorption bands in the FT spectrum of medium IR radiation shown in Table 1. Table 1 shows the range of maximum absorption bands positions for each of the 17 characteristic absorption bands. middle infrared band in the FT mid-IR spectrum of hydrated crystalline forms of lopinavir type I. This means that each hydrated crystalline form of lopinavir type I will have a maximum absorption band position within the range (minimum to maximum) given for each of the absorption bands listed in Table 1.

The most characteristic of the hydrated crystalline forms of lopinavir type I (including the substantially pure hydrated crystalline forms of lopinavir type I) are the positions of the mid-infrared absorption bands in the FT mid-IR spectrum for amide carbonyl vibrations. These absorbent bands for the hydrated forms of lopinavir type I lie in the range of 1652-1676 cm ^-1 and 1660-1616 cm ^-1 . Each hydrated crystalline form of lopinavir type I (including substantially pure hydrated crystalline forms of lopinavir type I) will have a maximum absorption band position of 1,652-1,666 cm ^-1 and an absorption band maximum of 1,626-1,615 cm -1. ¹ .

Hydrated crystalline forms of lopinavir type I (including substantially pure hydrated crystalline forms of lopinavir type I) are further characterized in the solid state by an infrared maximum absorption band at a position between 778-783 cm ^-1 , 765-769 cm ^-1 , 755- 759 cm ^-1 and 738 742 cm ^-1 .

Table 1

FT mid - solid state infrared band positions for hydrated crystalline forms of lopinavir type I

Minimum cm ^-1 Maximum cm ^-1 intensity * 3 495 3 505 W / absent 3 371 3 386 S / MS 3 281 3 299 MS 3 058 3 064 W 3 024 3 031 W 2 958 2 967 M 2 926 2 938 W 2 868 2 875 W 1 652 1 666 VS 1 606 1 615 S / MS 1 524 1 532 WITH

1 450 1 456 MS 1 404 1 410 W / VW 1 304 1 311 MS 1 187 1 197 MS 1 089 1 094 M 1 048 1 056 W

W = weak; M = medium; MS = moderate; S = strong; VS = very strong.

The crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule has the X-ray diffractogram shown in Figure 1. The crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule has a ¹³ C solid state nuclear magnetic resonance spectrum, FT spectrum near infrared radiation and the mid-infrared FT spectrum, as shown in Figures 2, 3 and 4, respectively. The infrared and nuclear magnetic resonance spectrum samples may contain slightly more than 0.5 molecules of water per lopinavir molecule relative to the lopinavir molecule. the hygroscopicity of the crystalline form when the level of hydration is about 0.5 molecules of water per lopinavir molecule.

As shown in Figure 1, the two-ate angle positions for the characteristic peaks in the X-ray diffraction pattern of a powdered hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule (including substantially pure hydrated crystalline forms of lopinavir containing about 0.5 molecules) water per lopinavir molecule) are: 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 °.

A hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule can be prepared from a hydrated crystalline form of lopinavir type I containing more than 0.5 molecules of water per lopinavir molecule by dehydration at 0% relative humidity. As long as dehydration continues from the hemihydrate stage, amorphous Iopinavir is obtained.

The hydrated crystalline form of lopinavir type I can be prepared from a solution or suspension in water or from solutions in mixtures with water and organic solvents miscible with water. Examples of water-miscible organic solvents include C 1 -C 4 alcohols such as methanol, ethanol and the like; acetonitrile; and so on. In the mixtures of water and organic solvent ^first

Water miscible, the water content may vary from about 10% by volume to about 90% by volume (preferably from about 40% to about 60% by volume). In a preferred method, the higher hydrated crystalline form of lopinavir type I can be prepared by crystallizing the hydrated lopinavir from a hot solution of a mixture of water and ethanol, followed by prolonged exposure to an environment with increased relative humidity.

In addition, the higher hydrated crystalline form of lopinavir type I may be prepared by hydrating the crystalline form of lopinavir type I hemihydrate at an elevated relative humidity (e.g., a relative humidity of about 20% or more%).

The above hydrated crystalline form of lopinavir type I has a powder X-ray diffraction pattern, a solid state ¹³ C nuclear magnetic resonance spectrum, a near solid infrared near-infrared FT spectrum and a medium solid infrared near-infrared FT spectrum shown in Figures 5, 6, 7 and 8, respectively.

As shown in Figure 5, the two-ate angle positions for the characteristic peaks in the X-ray diffraction pattern of the powdery higher hydrated crystalline form of lopinavir type I (including the substantially pure higher hydrated crystalline form of lopinavir) are: 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 °.

As shown in Figure 5, the higher hydrated crystalline form of lopinavir type I (including the substantially pure higher hydrated crystalline form of lopinavir) in the X-ray powder diffraction pattern is even better characterized by peaks having two-a-tilt angles: 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 single crystal x-ray parameters and experimental details for the higher hydrated crystalline form of lopinavir type I are as follows.

Single crystal X-ray parameters and experimental details for the higher hydrated crystalline form of lopinavir type I

Experimental details

Crystal data

Crystal system Grid parameters

Spatial group Z value Double counted

Measurement of intensity

diffractometer

radiation

temperature

20max

corrections

Number of measured reflections

Monoclinic a = 46,922 (2) bb = 13,9945 (4) cc = 11,7231 (4) = 105,605 (1) °

V = 7 414.2 (4) ^{3 3} C2 (# 5)

1.19 g / cm ³

Bruker SMART Mo Κα (λ = 0.7107 Å) neighborhood

46,6 ⁰

Lorentz polarization total: 27 795

Structure solution and refinement

Number of observations [I> 3.0 σ (I)] Number of variables Reflexion / ratio of parameters Residue: R; R _w

368

932

5.76

0,107; 0,128

In two further embodiments of the present invention, the solvated crystalline forms of lopinavir are solvated. Based on the single crystal X-ray structure determination, the first embodiment comprises forms of solvated lopinavir crystals comprising a crystal structure in which the bundles of lopinavir molecules are held in pile by hydrogen bonding interactions and arranged along a short crystallographic axis. Solvent molecules play no role in hydrogen bonding, but simply fill the pockets that exist between lopinavir molecule bundles. For identification purposes, solvated crystalline forms of lopinavir are referred to as type II in this embodiment.

Based on single crystal X-ray structure determination, the second embodiment comprises forms of solvated lopinavir crystals comprising a crystal structure in which lopinavir molecules are bound by hydrogen bridges in a manner such as leaves. The sheets of hydrogen bonded lopinavir molecules are wrinkled to form channels that are filled with varying amounts of solvent molecules. Solvent molecules in the hydrogen bonds of the second embodiment of the solvated crystal forms of lopinavir play no role. Because of. For identification purposes, solvated crystalline forms of lopinavir are referred to as type III in this embodiment.

Type II

The solvated crystalline forms of lopinavir type II are suitable for refining and isolating lopinavir during the final steps of the lopinavir preparation process.

The solvated crystalline forms of lopinavir type II are particularly valid for obtaining crystalline lopinavir which is free of or has a very reduced amount of various impurities that arise during the process of preparing lopinavir.

Solvated crystalline forms of lopinavir type II are typical hemisolvates. In other words, for each asymmetric crystal unit there are two lopinavir molecules and one solvent molecule. Lower level solvations are also possible. The solvated crystalline forms of lopinavir type II may be partially desolvated by vacuum drying or heating. However, if more than 75% of the maximum permissible solvent is removed (maximum permissible is hemisolvated), lopinavir amorphous is obtained. Thus, solvated crystalline forms of lopinavir type II contain from about 0.125 solvent molecules per lopinavir molecule to about 0.5 solvent molecules per lopinavir molecule.

The solvated crystalline forms of lopinavir type II contain relatively small polar organic solvents. Examples of such relatively small polar organic solvents include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, tert-pentanol, ethyl acetate, acetone, tetrahydrofuran, chloroform, propylene ethylene. , methyl (ethyl) ketone, dimethylsulfoxide and the like.

In a preferred embodiment, the solvated crystalline forms of lopinavir type II are substantially pure relative to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, unsalted and desolvated forms.

The FT mid-infrared solid state spectrum has been found to be a means of characterizing solvated crystalline forms of lopinavir type II and distinguishing solvated crystalline forms of lopinavir type II from other crystalline forms of lopinavir.

The solvated crystalline forms of lopinavir type II (including the substantially pure solvated crystalline forms of lopinavir type II) have the characteristic FT mid-IR solid state bands shown in Table 2. Table 2 shows the range of maximum absorption band positions for each of the 18 characteristic middle infrared radiation bands in FT mid-IR spectra of solvated crystalline forms of lopinavir type II. That is, each hydrated crystalline form of lopinavir type II will have a maximum absorption band position in the range (minimum to absorption band) for each of the maxima listed in Table 2.

The most characteristic of solvated crystalline forms of lopinavir type II (including the substantially pure solvated crystalline forms of lopinavir type I) are the mid-infrared band positions in the FT mid-IR spectrum for amide carbonyl vibrations. These strips for hydrated forms of lopinavir type II lie in the range of 1,661-1,673 cm ^-1 , 1,645-1,663 cm ^-1 and 1,619 1,629 cm ^-1 . Any solvated crystalline form of lopinavir type II (including substantially pure solvated crystalline forms of lopinavir type II) will have a maximum absorbent band at the 1661-1673 cm- ¹ position, a maximum at the 1645-1653 cm- ^{1 position,} and maximum at a position between 1619 and 1629 cm ^-1 .

Solvated crystalline forms of lopinavir type II (including substantially pure hydrated crystalline forms of lopinavir type II) are further characterized in the solid state by an infrared peak at a position at each range between 776-781 cm ^-1 , 767-771 cm ^-1 , 747-758 cm ¹ and 742-746 cm ^-1 .

Table 2

FT mid-range solid state infrared band positions for solvated crystalline forms of lopinavir type II

Minimum cm ^-1 Maximum cm ^-1 intensity * 3 391 3 415 M 3 324 3 340 MS 3 057 3 063 W 3 023 3 029 W 2 961 2 970 M 2 913 2 938 W

2 866 2 879 W 1 661 1 673 WITH 1 645 1 653 WITH 1 619 1 629 VS 1 540 1 548 MS. 1 514 1 522 WITH 1 450 1 456 MS 1 418 1 426 M 1 302 1 309 M 1 181 1 193 MS 1 089 1 095 M 1 045 1 056 W

• W = weak; M = medium; MS = moderate; S = strong; VS = very strong.

FT mid-IR spectra of solvated crystalline forms of lopinavir type II (isopropyl alcohol, ethyl acetate, chloroform) are shown in Figures 9, 10, 11, 12 and 13. FT near-IR spectra for solid state solvated crystalline forms of lopinavir type II (isopropyl alcohol) , ethyl acetate, chloroform) are shown in Figures 14, 15, 16, 17 and 18.

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

Solvated crystalline forms of lopinavir type II can also be prepared by cooling a supersaturated solution of lopinavir in a solvent, with or without the addition of seed crystals. The solvated crystalline form of lopinavir type II is then isolated by filtration.

Solvated crystalline forms of lopinavir type II can also be prepared by allowing the solvent to evaporate slowly from the lopinavir solution. The solvated crystalline form of lopinavir type II is then isolated by filtration.

Solvated crystalline forms of lopinavir type II may also be prepared by adding an antisolvent to the heated solution of lopinavir in a solvent to initiate crystallization. The solvated crystalline form of lopinavir type II is then isolated by filtration.

The single crystal x-ray parameters and experimental details for the hemisolvate of the crystalline form of lopinavir type II with ethyl acetate and the hemisolvate of the crystalline form of lopinavir type II with chloroform are as follows.

Single crystal X-ray parameters and experimental details for hemisolvate of crystalline form of lopinavir type II with ethyl acetate

Experimental details

Crystal data

Crystal system Grid parameters

Monoclinical

Spatial group Z value Double calculated

Measurement of intensity

diffractometer

radiation

temperature

20max

correction

Number of measured reflections a = 1 1.385 (1) bb = 33; 9490 (2) cc = 9.8641 (2) = 89.930 (1) °

W 3 = 799.37 (7) Å ³ P2 (# 4)

1.18 g / cm ³

Bruker SMART Mo Κα (λ = 0.7107 Å) neighborhood

46.7 °

Lorentz polarization total: 14 824 unambiguous: 5 211

Structure solution and refinement

Number of observations [I> 3.0 σ (Ι)] Number of variables Reflexion / ratio of parameters Residue: R; R _w

411,882 5.0

0.104; 0,099

Single crystal X-ray parameters and experimental details for hemisolvate of crystalline form of lopinavir type II with chloroform

Experimental details

Crystal data

Crystal system Grid parameters

orthorhombic

Spatial group Z value Double counted

Measurement of intensity

diffractometer

radiation

temperature

20max

correction

Number of measured reflections a = 9.7703 (51) Á b = 33.410 (2) Á c = 1 1.4874 (6) Á V = 3 749.8 (3) Á ³ Ρ2.2! 2 (# 18)

1.22 g / cm ³

Structure solution and refinement

Number of observations [I> 3.0 σ (Ι)]

234

Bruker SMART.

Mo Κα (λ = 0.7107 A) ambient

46.7 °

Lorentz polarization total: 14 960 unambiguous: 4 359

Number of Variables Reflection / Ratio of Residue Parameters: R; R _w

438

9.67

0,094; 0,104

Type III

The solvated crystalline forms of lopinavir type III are suitable for refining and isolating lopinavir during the final steps of the lopinavir preparation process.

The solvated crystalline forms of lopinavir type III are particularly valid for obtaining crystalline lopinavir which is free or has a very reduced amount of various impurities that arise during the preparation process of lopinavir.

Solvated crystalline forms of lopinavir type III are thermodynamically stable crystalline forms isolated from solvents that typically contain hydrophobic organic solvents or solvents too large to fit into the crystal lattice of the solvated crystalline form of lopinavir type II. Solvated crystalline forms of lopinavir type III include solvents including n-hexanol, n-octanol, 3-ethyl-3-pentanol, polyethylene glycol, ethyl acetate, isopropyl acetate, n-butyl acetate, glycerol triacetate, acetone, methyl (isobutyl) ketone, 2,4-dimethyl -pentanone, α-tetralone, methyl tert-butyl ether, 2,2,4,4-tetramethyltetrahydrofuran, dimethyl ether isosorbide, toluene, tetralin, nitrobenzene, p-xylene, sulfolane, hexane, heptane, decalin, oleic acid and the like .

In a preferred embodiment, the solvated crystalline forms of lopinavir type III are substantially pure with respect to other forms of lopinavir, including amorphous, hydrated forms, other solvated forms, unsalted and desolvated forms.

The FT mid-infrared solid state spectrum has been found to be a means to characterize solvated crystalline forms of lopinavir type III and to distinguish solvated crystalline forms of lopinavir type III from other crystalline forms of lopinavir.

Solvated crystalline forms of lopinavir type III (including substantially pure solvated crystalline forms of lopinavir type III) have the characteristic FT mid - solid state infrared bands shown in Table 3. Table 3 shows the maximum position ranges for each of the 16 characteristic mid mid IR infrared bands in FT mid - IR spectra of solvated crystalline forms of lopinavir type III. That is, each hydrated crystalline form of lopinavir type III will have a maximum absorption band position in the range (minimum to absorption band) for each of the maxima listed in Table 3.

The most characteristic of the solvated crystalline forms of lopinavir type III (including the substantially pure solvated crystalline forms of lopinavir type III) are band positions in the FT spectrum of mid-infrared radiation (midI) for amide carbonyl vibrations. The belt for hydrated forms of lopinavir type III lies in the range of 1,655-1,662 cm ^-1 . In many cases, for hydrated forms of lopinavir type III, the second band is located in the range of 1,636 1,647 cm ^-1 . In some cases, however, the second belt (in the range of 1636-1647 cm ^-1 ) appears as a shoulder on the first belt, or is not well separated from the first belt to be distinguishable as the second belt. Each solvated crystalline form of lopinavir type III (including substantially pure solvated crystalline forms of lopinavir type III) will have a maximum absorption band position of 1,655-1,662 cm ^-1 and may also have a maximum absorption band position of 1,636-1,667 cm ^-1 .

Solvated crystalline forms of lopinavir type III (including substantially pure hydrated crystalline forms of lopinavir type III) are further characterized in the solid state by an infrared peak at a position in each range between 772-776 cm ^-1 , 766-770 cm ^-1 and 743-747 cm ' ¹ .

As shown in Figure 31, the two-ate angle positions for the characteristic peaks in the X-ray diffraction pattern of the powdered solvated (ethyl acetate) crystalline form of lopinavir type III [including substantially pure solvated (ethyl acetate) crystalline forms of lopinavir] are: 4.85 ° ± 0, 1 °, 6.52 ° ± 0.1 °, 7.32 ° ± 0.1 °, 12.82 ° ± 0.1 °, 12.96 ° ± 0.1 °, 16.49 ° ± 0, 1 ° and 19.31 ° ± 0.1 °.

Table 3 v

Range of max positions in FT mid-IC solid state bands for solvated and desolvated crystalline forms of lopinavir type III

Minimum cm ^-1 maximum r-rv - " cm intensity * 3 394 3 405 WITH 3 378 3 302 MS 3 061 3 071 W 3 024 3 033 W 2 954 2 965 M 2 924 2 939 W 2 853 2 872 W 1 655 1 662 VS 1 636 1 647 WITH 1 517 1 525 WITH 1 501 1 513 MS 1 450 1 455 MS 1 300 1 309 MS 1 193 1 200 MS 1090 1 098 W 1 051 1 057 M

• W = weak; M = medium; MS = moderate; S = strong; VS = very strong.

The FT mid-solid spectrum of the ethyl acetate solvated crystalline form of lopinavir type III is shown in Figure 19. The near-infrared spectrum for the solid state of the ethyl acetate solvated crystalline form of lopinavir type III is shown in Figure 20.

Solvated crystalline forms of lopinavir type III can be prepared by suspending an excess of solid lopinavir in a solvent and allowing the suspension to equilibrate over time. The solvated crystalline form of lopinavir type III is then isolated by filtration.

Solvated crystalline forms of lopinavir type III can also be prepared by cooling a supersaturated solution of lopinavir in a solvent with or without the addition of seed crystals. The solvated crystalline form of lopinavir type III is then isolated by filtration.

Solvated crystalline forms of lopinavir type III can also be prepared by allowing the solvent to evaporate slowly from the lopinavir solution. The solvated crystalline form of lopinavir type III is then isolated by filtration.

Solvated crystalline forms of lopinavir type III can also be prepared by adding an antisolvent to the heated solution of lopinavir in a solvent to initiate crystallization. The solvated crystalline form of lopinavir type III is then isolated by filtration.

Single crystal X-ray parameters and experimental details for ethyl acetate solvated crystalline form of lopinavir type III

Experimental details

Crystal data

Crystal system Grid parameters

Spatial group Z value

Measurement of intensity

diffractometer

radiation

temperature

20max

Ortorombic a = 23,961 (9) A b = 27,58 (1) A c = 11,967 (4) A v = 7 907 (5) A ³ C222i (# 20)

Rigaku AFC5R

Cu Κα (λ = 1.54178 Å) surroundings

120.2 ⁰

corrections

Number of measured reflections

Structure solution and refinement

Number of observations [I> 3.0 σ (Ι)] Number of variables Reflexion / ratio of parameters Residue: R; R _w

Lorentz polarization Absorption (trans. Factors: 0.87 - 1.00) total: 6 520 unambiguous: 6 520

154

443

4.86

0,096; 0,093

One example of the desolvated crystalline form of lopinavir type III was prepared from acetonitrile. Of all other solvents, the fully desolvated crystalline form of lopinavir type III could not be prepared.

The desolvated crystalline form of lopinavir type III is useful in refining and isolating lopinavir and in preparing pharmaceutical compositions for administration of lopinavir.

The FT mid-infrared solid state spectrum has been found to be a means to characterize desolvated crystalline forms of lopinavir type III and to distinguish desolvated crystalline forms of lopinavir type III from other crystalline forms of lopinavir except for solvated crystalline form III.

The desolvated crystalline form of lopinavir type III (including the substantially pure desolvated crystalline form of lopinavir type III) also has the characteristic absorption bands in the FT mid-IC solid state spectrum shown in the Table.

Table 3 shows the range of maximum positions for each of the 16 characteristic absorbing bands of medium infrared radiation in the FT mid-IR spectrum of the desolvated crystalline form of lopinavir type III. That is, the desolvated crystalline form of lopinavir type III will have a maximum position within the 19 range (from minimum to absorption band) given for each of the absorption bands listed in Table 3.

The most characteristic of the desolvated crystalline form of lopinavir type III (including the substantially pure solvated crystalline form of lopinavir type III) are the positions of the mid-infrared absorption bands in the FT mid-IR spectrum for amide carbonyl vibrations. For the desolvated crystalline form of lopinavir type III, the band lies in the range of 1,655-1,662 cm ^-1 . In many cases, for desolvated forms of lopinavir type III, a second band (ranging from 1636-1647 cm ^-1 ) appears as a shoulder on the first band or is not well separated from the first band to be distinguishable as the second band. Any desolvated crystalline form of lopinavir type III (including the substantially pure solvated crystalline form of lopinavir type III) will have a maximum position within the range of 1,655-1,662 cm ^-1 and may also have a maximum position within the range of 1,636-1,647 cm ^-1 as the maximum shoulder at the position of 1,655 1,662 cm ^-1 .

The FT solid-state IR spectrum of the desolvated crystalline form of lopinavir type III is shown in Figure 21. The near-infrared solid state IR spectrum of the desolvated crystalline form of lopinavir type III is shown in Figure 22. The X-ray diffractogram of the desolvated crystalline form of lopinavir type III is powdered. Figure 23. The solid state ¹³ C NMR spectrum of the desolvated crystalline form of lopinavir type III is shown in Figure 24. The solid state DSC thermogram of the desolvated crystalline form of lopinavir type III is shown in Figure 25.

When differential scanning calorimetry is performed with a scan rate of 1 ° C / min to 150 ° C for a sample that has lost 0.0% of its original weight after heating at 1 ° C / min to 150 ° C, the DSC shows a solid state thermogram of desolvated crystalline forms of lopinavir type III melting endotherm starting at 95 ° C and peaking at 98 ° C (ΔΗ = 18 J / g).

As shown in Figure 23, the two-ate angle positions for the characteristic peaks in the X-ray diffraction pattern of lopinavir type III desolvated crystalline form20 (including the substantially pure desolvated crystalline form of lopinavir type III) are: 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 °.

More preferably, as shown in Figure 23, the desolvated crystalline form of lopinavir type III (including the substantially pure desalinated crystalline form of lopinavir type III) in the X-ray diffraction pattern of the powder form is characterized by peaks having two-ata angle positions: 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 °.

Single crystal X-ray parameters and experimental details for the desolvated crystalline form of lopinavir type III

Experimental details

Crystal data

Crystal system Grid parameters

Spatial group Z value TwoCounted

Ortorombic a = 24.0465 (10) Å b = 27.5018 (1 1) = c = 1 1.9744 (3) V V = 7 918.9 (8) ^{3 3} C222, (# 20)

1.055 g / cm ³

Measurement of intensity

diffractometer

radiation

temperature

20max

Number of measured reflections

Nonius KappaCCD

Mo K α (λ = 0,71073 Å) neighborhood ⁰ total: 28 494

Structure solution and refinement

Number of observations [I> 2.0 σ (I)] Number of variables Reflection / ratio of parameters Residue: R; R _w unambiguous: 5 148

069

442

9.21

0,056; 0,116

In another embodiment of the present invention, there is an unsolvated crystalline form of lopinavir. For identification, the unsolvated crystalline form of lopinavir of this embodiment is referred to as type IV.

The unsolvated crystalline form of lopinavir type IV is useful in refining and isolating lopinavir and in preparing pharmaceutical compositions for administration of lopinavir.

In a preferred embodiment, the solvated crystalline forms of lopinavir type IV are substantially pure relative to other forms of lopinavir, including amorphous, hydrated forms, solvated forms, unsolvated and desolvated forms.

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

The unsolvated crystalline form of lopinavir type IV (including the substantially pure unsolvated crystalline form of lopinavir type IV) has the characteristic absorption bands in the FT mid - solid state infrared spectrum shown in Table 4. Table 4 shows the maximum position ranges for each of the 19 characteristic IR bands. in the FT mid-IR spectrum of the unsolvated crystalline form of lopinavir type IV. This means that any unsolvated crystalline form of lopinavir type IV will have a maximum absorption band position in the range (minimum to maximum) given for each of the maximums in Table 4. If the mid-IR spectrum is scanned at 4 cm ^-1 , it may be also the maximum of the following other characteristic bands recorded in one or more positions: 1,668-1,674 cm ^-1 (strong), 1,656-1,662 cm ^-1 (strong), 1,642-1,648 cm ^-1 (strong). At higher resolution or after Fourier transformation, these additional absorbent bands are distinguishable.

The most characteristic of the unsolvated crystalline form of lopinavir type IV (including the substantially pure solvated crystalline forms of lopinavir type IV) are the positions of the medium infrared band in the solid-state FT mid-IR spectrum for amide carbonyl vibrations. These bands for unsolvated forms of lopinavir type IV lie in the range of 1,680-1,685 cm ^-1 and 1,625 1,630 cm ^-1 . In addition, in particular at higher resolutions, the strips are located within the range of 1,668-1,674 cm ^-1 , 1,656-1,662 cm ^-1 and 1,642-1,648 cm ^-1 . Any unsolvated crystalline form of lopinavir type IV (including substantially pure unsolvated crystalline forms of lopinavir type IV) will have a maximum absorption band position of 1,680-1,685 cm ^-1 , a maximum position of 1,625-1,630 cm ^-1 and may also have a maximum in the position between 1,668-1,674 cm ^-1 , a maximum in the range 1,656-1,662 and cm ^-1 and a maximum between 1,642-1,648 and cm ^-1 .

The unsolvated crystalline form of lopinavir type IV (including the substantially pure unsolvated crystalline form of lopinavir type IV) is characterized in the solid state by an infrared maximum at a position between 780-784 cm ^-1 , 764-768 cm ^-1 and 745-749 cm in the solid state. ' ¹ .

Table 4

FT mid-range solid state infrared range for unsolvated crystalline form of lopinavir type IV

Minimum cm ^-1 Maximum cm ^-1 intensity * 3 433 3 439 M 3 415 3 421 M 3 406 3 412 M 3 338 3 345 MS

3 309 3 315 M 3 272 3 278 M 3 082 3 089 W 3 025 3 030 W 2 959 2 965 M 2 926 2 932 W 2 870 2 875 W 1 680 1 685 WITH 1 625 1 630 VS 1 514 1 526 WITH 1 451 1 456 MS 1 306 1 312 M 1 189 1 194 M 1 089 1 094 W 1 044 1 050 M

• W = weak; M = medium; MS = moderate; S = strong; VS = very strong.

The unsolvated crystalline form of lopinavir type IV has an FT infrared spectrum, near infrared FT spectrum, a powder X-ray diffraction pattern, a solid state ¹³ C NMR spectrum and a differential scanning calorimetry (DSC) thermogram shown in Figures 26, 27, 28, 28, 28, 28, and 30 respectively.

As shown in Figure 28, the two-ate angle positions for the characteristic peaks in the X-ray diffraction pattern of the powdered unsolvated crystalline form of lopinavir type IV (including the substantially pure unsolvated crystalline form of lopinavir type IV) are: 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 °.

More preferably, as shown in Figure 28, the unsolvated crystalline form of lopinavir type IV (including the substantially pure unsolvated crystalline form of lopinavir type IV) in the X-ray powder diffraction pattern is characterized by peaks having the following two-ata angle positions: 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 °.

When differential scanning calorimetry is performed with a scan rate of 1 ° C / min to 150 ° C, the DSC shows a solid state thermogram of the unsolvated crystalline form of lopinavir type IV melting endotherm beginning at 117 ° C and peaking at 122 ° C (ΔΗ = 47 J / g).

The single crystal x-ray parameters and experimental details for the unsolvated crystalline form of lopinavir type IV are as follows:

Single crystal X-ray parameters and experimental details for unsolvated crystalline form of lopinavir type IV

Experimental details

Crystal data

Crystal system Grid parameters

Spatial group Z value Dycalculated

Measurement of intensity

diffractometer

radiation

temperature

26max

correction

Ortorombic a = 15,065 (8) Å b = 25,27 (1) Å c = 9,732 (3) Å = 3 704 (3) Å ³ P2i2,2i (# 20)

1.13 g / cm ³

Number of measured reflections

RigakuAFC5R

Cu K α (λ = 1,54178 Å) of the surroundings 120,2 °

Lorentz polarization

Absorption (trans. Factors:

0.8362 - 0.9496) total: 3,145

Structure solution and refinement

Number of observations [I> 3.0σ (Ι)] Number of variables Reflexion / ratio of parameters Residue: R; R _w

434

415

3.46

0,081; 0,085

The unsolvated crystalline form of lopinavir type IV can be prepared from acetonitrile by slow cooling and slow evaporation of the saturated solution or by exposing amorphous lopinavir to the acetonitrile atmosphere. In addition, to obtain more unsolvated crystalline form of lopinavir type IV, a solution of lopinavir in acetonitrile may be seeded with crystals of the unsolvated crystalline form of lopinavir type IV.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of a hydrated crystalline form of lopinavir type I containing about 0.5 water molecules per molecule of lopinavir.

Figure 2 is the 100 MHz solid state ¹³ C nuclear magnetic resonance spectrum of a hydrated crystalline form of lopinavir type I containing about 0.5 water molecules per lopinavir molecule.

Figure 3 is a near-infrared FT spectrum of the hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per solid molecule of lopinavir.

Figure 4 is the FT spectrum in the mid-infrared region of the hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per solid molecule of lopinavir.

Figure 5 is an X-ray powder diffraction pattern of the above hydrated crystalline form of lopinavir type I;

Figure 6 is a 100 MHz solid state ¹³ C nuclear magnetic resonance spectrum of the higher hydrated crystalline form of lopinavir type I.

Figure 7 is a near-infrared FT spectrum of the solid state hydrated crystalline form of lopinavir type I.

Figure 8 is the FT spectrum in the central infrared region of the above hydrated crystalline form of solid-state lopinavir type I.

Figure 9 is a FT spectrum in the middle infrared region of the hemisolvate of the crystalline form of lopinavir type II with solid isopropyl alcohol.

Figure 10 is a FT spectrum in the middle infrared region of the hemisolvate of the crystalline form of lopinavir type II with isopropyl alcohol in solid form having 2% solvent by thermogravimetry.

Figure 11 is the FT spectrum in the mid-infrared region of the hemisolvate of the crystalline form of lopinavir type II with solid state ethyl acetate.

Figure 12 is an FT spectrum in the middle infrared region of hemisolvate of the crystalline form of lopinavir type II with solid state ethyl acetate having less than 0.5 moles of ethyl acetate per 2 moles of lopinavir by thermogravimetry.

Figure 13 is the FT spectrum in the mid-infrared region of the hemisolvate of the crystalline form of lopinavir type II with solid chloroform.

Figure 14 is a near-infrared FT spectrum of the hemisolvate of the crystalline form of lopinavir type II with solid isopropyl alcohol.

Figure 15 is a near-infrared FT spectrum of the hemisolvate of the crystalline form of lopinavir type II with isopropyl alcohol in the solid state having 2% solvent by thermogravimetry.

Figure 16 is a near-infrared FT spectrum of the hemisolvate of the crystalline form of lopinavir type II with solid state ethyl acetate.

Figure 17 is a near-infrared FT spectrum of the hemisolvate of the crystalline form of lopinavir type II with solid state ethyl acetate having less than 0.5 moles of ethyl acetate per 2 moles of lopinavir by thermogravimetry.

Figure 18 is a near-infrared FT spectrum of the hemisolvate of the crystalline form of solid-state lopinavir type II.

Figure 19 is a solid state FT spectrum in the middle infrared region of the ethyl acetate solvated crystalline form of lopinavir type III.

Figure 20 is the near-infrared FT spectrum of the solid state ethyl acetate solvated crystalline form of lopinavir type III.

Figure 21 is a solid state FT spectrum in the middle infrared region of the desolvated crystalline form of lopinavir type III.

Figure 22 is a near-infrared FT spectrum of the solid state of the desolvated crystalline form of lopinavir type III.

Figure 23 is an X-ray powder diffraction pattern of desolvated crystalline form of lopinavir type III.

Figure 24 is the 100 MHz solid state nuclear magnetic resonance spectrum C of the desolvated crystalline form of lopinavir type III.

Figure 25 is a differential scanning calorimetry (DSC) thermogram for the desolvated crystalline form of lopinavir type III.

Figure 26 is the FT spectrum in the mid-infrared region of solid unsolvated crystalline form of lopinavir type IV.

Figure 27 is the near-infrared FT spectrum of the unsolvated crystalline form of solid-state lopinavir type IV.

Figure 28 is an X-ray powder diffraction pattern of unsolvated crystalline form of lopinavir type IV.

Figure 29 is a 100 MHz solid-state ¹³ C nuclear magnetic resonance spectrum of the unsolvated crystalline form of lopinavir type IV.

Figure 30 is a differential scanning caiorimetry (DSC) thermogram for the unsolvated crystalline form of lopinavir type IV.

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

The following examples will serve to further illustrate the preparation of the novel crystalline forms of lopinavir of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of the above hydrated crystalline form of lopinavir type I

In a mixture of 20 ml of ethanol and 40 ml of water, a saturated solution of lopinavir was prepared at room temperature. The saturated solution was stirred at room temperature and water (54 mL) was slowly added via a syringe pump at a rate of 0.15 mL / min. After stirring overnight, the precipitate (crystals) was filtered off with suction.

Example 2

Preparation of the above hydrated crystalline form of lopinavir type I

The NMR tube was charged with 1.75 mL of water. The water level was then carefully overlaid with a 0.5 ml solution of lopinavir in ethanol (99.482 mg lopinavir in ml ethanol). The tube was stoppered to prevent evaporation and allowed to stand undisturbed. Crystals of the hydrated crystalline form of lopinavir type I containing more than 0.5 molecules of water per molecule of lopinavir were obtained after about 30 days.

Example 3

Preparation of the above hydrated crystalline form of lopinavir type I

Lopinavir (30 g) was dissolved in a mixture of 360 ml deionized distilled water and 418 ml 96% ethanol by heating at about 60 ° C with gentle stirring. The hot solution was filtered to remove undissolved material. The filtrate was slowly cooled with gentle stirring to room temperature and at this stage was seeded with about 50 mg of the product of Example 1. The mixture was stirred at room temperature for 3 days at moderate speed. The resulting mixture was filtered under vacuum. The filtered solid was transferred to filter paper and any lumps were crushed by gentle manipulation with a spatula. 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 twelve daily drying at room temperature (24 ± 1 ° C) and 75% relative humidity, about 20.5 g of the desired hydrated crystalline form of lopinavir was obtained. Powder X-ray diffractogram (Fig. 5), 100 MHz solid state nuclear magnetic resonance ¹³ C spectrum (Fig. 6), near-infrared solid-state FT spectrum (Fig. 7), mid-solid-infrared solid state FT spectrum (Fig. 8) . According to thermogravimetry, the product contained 4.3% volatiles.

Example 4

Preparation of a hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule

The product of Example 3 (about 100 mg) was filled into a sample holder of a powder X-ray diffractometer equipped with a controlled atmosphere chamber of the sample and a heated pad. The sample was heated to 1 ° C / min at 30 ° C under a dry nitrogen atmosphere and maintained at this temperature. Conversion to hemihydrate was complete in 60-90 minutes. X-ray powder diffraction pattern (Fig. 1).

Example 5

Preparation of a hydrated crystalline form of lopinavir type I containing about 0.5 molecules of water per lopinavir molecule

The product of Example 3 (1g) was placed in a thin layer in a polypropylene weighing vessel and dried overnight at room temperature in a vacuum oven at about -65 kPa. The resulting hygroscopic product (lopinavir hemihydrate) was transferred to glass vials and dried again for 6 hours at ambient temperature at about -65 kPa. The vials were then rapidly sealed with polypropylene stoppers and stored in a desiccator over anhydrous calcium sulfate. 100 MHz solid state ¹³ C nuclear magnetic resonance spectrum (Fig. 2), near-infrared solid state FT spectrum (Fig. 3), solid-state mid-infrared FT spectrum (Fig. 4). According to thermogravimetry, the product contained 2% volatiles.

Example 6

Preparation of the hemisolvate of the crystalline form of lopinavir with isopropyl alcohol type II

Lopinavir (16 g) was dissolved in 50 ml of isopropyl alcohol by heating the mixture on a heated plate to boiling while stirring with a magnetic stirrer. The solution was then cooled to room temperature and a precipitate formed. The resulting mixture was stirred at room temperature for 24 hours with enough stirring to keep the precipitate in suspension. The precipitate was collected by suction and air dried to give 9.9 g of the hemisolvate of the crystalline form of lopinavir type II with isopropyl alcohol. Thermogravimetry of the product indicated the presence of volatile fractions corresponding to 1 mole of isopropyl alcohol per two moles of lopinavir. Powder X-ray analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvated crystalline form of lopinavir type II. FT spectrum of the middle solid infrared region (Fig. 9). FT spectrum near solid-state infrared region (Fig. 14).

Example Ί

Preparation of a solvate of the crystalline form of lopinavir with isopropyl alcohol type II (1.6 wt% isopropyl alcohol by thermogravimetry)

Lopinavir (16 g) was suspended in 2.5 ml of isopropyl alcohol in a glass vial containing four 4 mm diameter glass beads to promote stirring. The vial was sealed and the suspension was inverted from one end to the other at room temperature for four 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 then heated to 50 ° C and the sample was dried at -65 kPa and at 50 ° C for 25 days to give the title compound. According to thermogravimetry, the product contained 1.6% volatiles.

Example 7

Preparation of a solvate of the crystalline form of lopinavir with isopropyl alcohol type II (2 wt% isopropyl alcohol by thermogravimetry)

A sample of the product of Example 6 was rinsed with heptane and then rotary evaporated for two days. The residue was transferred to a petri dish and dried in a vacuum oven, which was then heated to 50 ° C and the sample was dried at -65 kPa and at 50 ° C for 3 days to give the title compound. According to thermogravimetry, the product contained 2% volatiles. FT spectrum of the middle solid infrared region (Fig. 10). FT spectrum near solid-state infrared region (Fig. 15).

Example 9

Preparation of the hemisolvate of the crystalline form of lopinavir with ethyl acetate type II

Example 9A

Preparation of crude lopinavir

Crude lopinavir prepared according to U.S. Pat. U.S. Patent No. 5,201,516; 5,914332 (Example 38) from (S) -pyroglutamic acid salt and (2S, 3S, 5S) -2-amino-3-hydroxy-5- [2S- (1, tetrahydropyrimid-2-onyl) -3-methylbutanoyl The amino-1,6-diphenylhexane (about 85 g, corrected for solvent content) was dissolved in 318.5 g of ethyl acetate, and the solution was concentrated to an oil in vacuo. The residue was dissolved in 225 g of ethyl acetate and concentrated in vacuo to an oil a second time. The residue was dissolved in ethyl acetate (approximately 300 mL) at 65 ° C, filtered to remove traces of undissolved solids and concentrated in vacuo to a foam. The foam was dissolved in 338 g of ethyl acetate and this solution was divided into four equal portions.

Example 9B

Preparation of the hemisolvate of the crystalline form of lopinavir with ethyl acetate type II

One part of the lopinavir solution prepared in Example 9A was concentrated in vacuo to an oil and then dissolved in 50 mL of absolute ethanol. The solvent was evaporated in vacuo. The residue was kept under vacuum with heating (approximately 50 ° C - 60 ° C) for an additional 30 minutes. The resulting foam was dissolved in ethyl acetate (87 mL) at ambient temperature. After less than five minutes of stirring, solid particles were evident. The resulting slurry was stirred for 16 hours and then diluted with 87 mL of heptane. After three hours, the solids were collected by filtration, washed with 36 mL of AcOEt / heptane (1: 1 by volume) and dried under vacuum at 60 ° C for 72 hours to give 19.4 g of lopinavir hemisolvate with type II ethyl acetate. FT spectrum of the middle solid infrared region (Fig. 11). FT spectrum near solid infrared region (Fig. 16). According to thermogravimetry, the product contained 4.4% volatiles.

Example 9C

Alternative preparation of hemisolvate of the crystalline form of lopinavir with ethyl acetate type II

Crude lopinavir prepared according to U.S. Pat. U.S. Patent No. 5,201,516; 5,914332 (Example 38) from (S) -pyroglutamic acid salt and (2S, 3S, 5S) -2-amino-3-hydroxy-5- [2S- (tetrahydro-pyrimidin-2-onyl) -3-methylbutanoyl] amino 1,6-diphenylhexane (about 20 g, corrected for solvent content) was dissolved in 118 g ethyl acetate and then concentrated in vacuo to an oil. The residue was dissolved in 95.7 g of ethyl acetate at 46 ° C and then concentrated in vacuo to an oil. The residue was dissolved in 95.8 g of ethyl acetate at 64 ° C. Moisture measurement with KF 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 for 10 minutes. The mixture was stirred at 15 ° C and stirred at 15 ° C - 18 ° C for 1.5 hours. The solids were collected by filtration, washed with 13.3 g of ethyl acetate, dried under vacuum at 56 ° C - 58 ° C for 16 hours, and yielded 12.3 g of lopinavir hemisolvate with type II ethyl acetate.

Example 10A

Preparation of a solvate of the crystalline form of lopinavir with type II ethyl acetate (having less than 0.5 mol of ethyl acetate per 2 moles of lopinavir by thermogravimetry)

One part of the lopinavir solution prepared in Example 9A was concentrated in vacuo to an oil and then dissolved in 50 mL of absolute ethanol. The solvent was evaporated in vacuo. The residue was kept under vacuum with heating (approximately 50 ° C - 60 ° C). another 30 minutes. Crystals of the product of Example 9B were added to the resulting foam as seed crystals. The foamy residue was dissolved in ethyl acetate (87 mL) at ambient temperature. After less than five minutes of stirring, solid particles were evident. The resulting slurry was stirred for 16 hours and then diluted with 87 mL of heptane. After three hours, the solids were collected by filtration, washed with 36 mL of AcOEt / heptane (1: 1 v / v v / v) and dried under vacuum at 60 ° C for 72 hours to give 19.37 g of lopinavir-ethyl acetate type II solvate. FT spectrum of the middle solid state infrared region (Fig. 12). FT spectrum near solid-state infrared region (Fig. 17). According to thermogravimetry, the product contained 1.7% volatiles.

Example 10B

Alternative preparation of solvate of crystalline form of lopinavir with type II ethyl acetate (having less than 0.5 mole of ethyl acetate per 2 moles of lopinavir by thermogravimetry)

A crude lopinavir solution prepared according to U.S. Pat. U.S. Patent No. 5,201,516; 5,914332 (Example 2; reaction of 17 g of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane with 8 g of 2S- (1-tetrahydropyrimide) (2-yl) -3-methylbutane via EDAC / HOBT reaction) in isopropyl acetate (about 250 mL) and concentrated in vacuo to an oil. The residue was dissolved in 250 mL of ethyl acetate and concentrated in vacuo to a foam. The foam was dissolved in 120 mL of warm ethyl acetate. The solution was divided into three portions each

44,9 g. The solutions were cooled to ambient temperature at which rapid crystallization occurred. One of these was stirred overnight at ambient temperature. The solids were collected by filtration, washed with 8 mL of ethyl acetate, dried under vacuum at 22 ° C for 40 hours, then dried under vacuum at 70 ° C for 44 hours, to give 6.23 g of lopinavir-ethyl acetate type II solvate.

Example 11

Preparation of the hemisolvate of the crystalline form of lopinavir with chloroform type II

Lopinavir (10 g) was dissolved in 30 ml of chloroform. The solution was then heated to boiling on a hot plate while stirring with a magnetic stirrer. After reducing the volume of the solution to about half the initial volume, about 10 mL of n-heptane was added dropwise until the solution became cloudy.

About 30 ml of chloroform was then added and the cooking was continued until the volume was again about half the initial volume. About 20 ml of chloroform was then added and boiling was continued until the volume was again about half the initial volume. The mixture was then slowly cooled to room temperature and allowed to partially evaporate. After slow evaporation, a glassy residue of syrup-like consistency remained. This was mixed with about 20 ml of chloroform and heated on a heating plate. Then n-heptane was added dropwise until a precipitate began to form. The precipitate was dissolved by reheating the mixture. The warm solution was transferred to a beaker which was placed in a container 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 beaker contents. When this mixture was allowed to stand for about 1 hour, several needle-like crystals formed. More heptane (about 40 mL) was added to the beaker containing vessel, sealed and allowed to stand. After one day the beaker contained a large amount of crystals. The crystals were isolated by aspiration. The crystalline mass was finely crushed using a spatula, and the crystals were washed with a mixture of chloroform and heptane from a vessel near the beaker in which the crystals grew. Thermogravimetry of the product showed the presence of a volatile fraction corresponding to 1 mole of chloroform for every two moles of lopinavir. Powder X-ray analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product was a solvated crystalline form of lopinavir type II. FT spectrum of the middle solid infrared region (Fig. 13). FT spectrum near solid-state infrared region (Fig. 18).

Example 12

Preparation of ethyl acetate solvated crystalline form of lopinavir type III

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 and solid particles were evident at this stage. The slurry was cooled to 35 ° C in 30 minutes and then stirred for one hour. Then the slurry was cooled to 15 ° C in 13 minutes and then stirred for one hour. Heptane (25.1 g) was added dropwise over 13 minutes. The resulting slurry was stirred for 30 min. The resulting solids were collected by filtration, washed with ethyl acetate / heptane (1: 1 v / v, 20 mL), dried at 62 ° C under vacuum for 20 hours to give 6.4 g of the title compound. Powder X-ray analysis confirmed that the product was crystalline and infrared spectroscopy confirmed that the product was a solvated crystalline form of lopinavir type III. FT spectrum of the middle solid state infrared region (Fig. 19). FT spectrum near solid infrared region (Fig. 20). According to thermogravimetry, the product contained 2.3% volatiles.

Example 13

Preparation of ethyl acetate solvated crystalline form of lopinavir type III

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

Example 14

Preparation of ethyl acetate solvated crystalline form of lopinavir type III

One aliquot of the lopinavir solution prepared in Example 9A was diluted

14.8 g of ethyl acetate and heated to 70 ° C-75 ° C, then diluted with 75 g of heptanes maintaining an internal temperature of greater than 70 ° C. The resulting solution was heated at 75 ° C for 15 min and then allowed to gradually cool to ambient temperature. After stirring at ambient temperature overnight, the solids were collected by filtration, washed with 36 mL of ethyl acetate / heptanes (1: 1 by volume) and dried at 60 ° C under vacuum for 72 hours to give 21.5 g of the title compound.

Example 15

Preparation of the desolvated crystalline form of lopinavir type III

Lopinavir (5g) was placed in a 100 ml beaker. Just enough acetonitrile was added to dissolve about 95% of lopinavir. The beaker was placed in a container containing an approximately 1 cm deep layer of anhydrous calcium sulfate (DRIERITE). The vessel was sealed and the material was allowed to stand undisturbed at ambient temperature. After standing 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 and this was finely crushed with a spatula. The solids were collected by suction and rinsed with about 1 mL of acetonitrile. The solid was transferred to a Petri dish, dried at ambient temperature in vacuo to give a desolvated crystalline form of lopinavir type III. Powder X-ray analysis confirmed that the product was crystalline and infrared spectrometry confirmed that the product is a crystalline form of lopinavir type III. According to thermogravimetry, the product contained less than 0.05% volatiles. FT spectrum of the middle solid infrared region (Fig. 21). FT spectrum near solid state infrared region (Fig. 22). Powder X-ray diffractogram (Fig. 23). 100 MHz ¹³ C solid state nuclear magnetic resonance spectrum (Fig. 24). DSC thermogram (Fig. 25).

Example 16

Preparation of unsolvated crystalline form of lopinavir type IV

Lopinavir (amorphous, 1 g) was placed in the crystallization dish (A). This dish was placed in a larger crystallization dish (B) containing about 10 ml of acetonitrile and placed on a heating plate. Medium size crystallization dish (C) was inverted and placed over dish A but still inside the dish

B. An inverted large crystallization dish D was placed over plates A, B, and C. The heating plate was heated to about 35 ° C and then the heating plate was turned off. The whole arrangement was then left in the laboratory at ambient temperature for 10 days. After 10 days, all acetonitrile was evaporated.

A portion of the resulting crystalline product (0.1 g) was mixed with acetonitrile (0.6 mL) and stirred for 1 hour. The mixture was filtered, the solid was air-dried to give the unsolvated crystalline form of lopinavir type IV.

Example 17

Preparation of unsolvated crystalline form of lopinavir type IV

Lopinavir (259 g) was dissolved in 500 g acetonitrile at 40 ° C - 42 ° C. The turbid solution was filtered through a 0.45 µ nylon membrane into a 2 L round bottom flask and seeded with several crystals of the product of Example 16. The flask was at 10-20 rpm. rotated overnight on a rotary evaporator without heating or vacuum. The resulting thick slurry of needle-like crystals. The slurry was cooled in an ice bath for 1 hour and then filtered on a nitrogen-protected filter and covered with a plastic film. The filter cake was washed with acetonitrile and vacuum dried to dryness under nitrogen for 30 minutes. The filter cake was then transferred to a crystallization dish and dried at 60 ° C-65 ° C over the weekend at 20-21 Hg (= 508-635 mm Hg = 67.7-84.7 kPa) at 60 ° C-65 ° C to give 194, 3 g of unsolvated crystalline form of lopinavir type IV. According to powder X-ray diffraction, the product was crystalline and was classified as the unsolvated crystalline form of lopinavir type IV FT by solid-state medium infrared infrared spectrometry. FT spectrum of the middle solid infrared region (Fig. 26). FT spectrum near solid-state infrared region (Fig. 27). Powder X-ray diffractogram (Fig. 28). 100 MHz solid state nuclear magnetic resonance spectrum C (Fig. 29). DSC thermogram (Fig. 30). According to thermogravimetry, the product contained less than 0.1% volatiles.

When administered in the treatment of HIV infection, lopinavir is best administered in combination with 1: 1 ritonavir (lopinavir: ritonavir). A preferred pharmaceutical composition for administration of lopinavir comprising a 1: 1 ratio of lopinavir to ritonavir encapsulated in a soft elastic gelatin capsule has the following composition:

lopinavir 133.3 mg ritonavir 33.3 mg Oleic acid, NF 598.6 mg Propylene glycol, USP 64.1 mg Polyoxyl 35 Castor Oil, NF 21.4 mg

(Cremephor EL®)

Water, purified, USP (distilled) 4.3 mg

When a hydrated or solvated form of lopinavir is used in the composition, the amount of the hydrated or solvated form of lopinavir is adjusted by including the amount of water or other solvents present in crystalline form.

A preferred composition may be prepared as follows. The following prescription is used to prepare 1,000 soft gelatin capsules:

measure (mg / capsule) Title number (G) As needed Nitrogen, NF As needed 578.6 Oleic acid, NF 578.6 33.3 ritonavir 33.3 64.1 Propylene glycol, USP 64.1 4.3 Water, purified, USP (distilled) 4.3 133.3 lopinavir 133.3 10,0 Oleic acid, NF 10,0 21.4 Polyoxyl 35 Castor Oil, NF 21.4 10,0 Oleic acid, NF 10,0

The mixing tank and suitable container are purged with nitrogen. 578.6 g of oleic acid was then charged to the mixing tank. The mixing tank is heated to 28 ° C (not to exceed 31 ° C) and mixing is started. Then 33.3 g of ritonavir is added to the oleic acid with stirring. Glycol and water are added to the mixing tank and stirring is continued until the solution becomes clear. 133.3 g of lopinavir are then added to the mixing tank and stirring is continued. 10 g of oleic acid are then added to the tank and stirring is continued until the solution becomes clear. To this, 21.4 g of polyoxylated castor oil (Polyoxyl 35 Castor Oil NF) are added while stirring, followed by 10 g of oleic acid. The solution is stored at 2 ° C - 8 ° C until encapsulation. Each soft gelatin capsule is filled with 0.855 g of solution and the soft gelatin capsule is then dried and stored at 2 ° C - 8 ° C.

As used herein, the term substantially pure in relation to the crystalline form of lopinavir refers to that crystalline form of lopinavir which is more than about 90% pure. That is, the crystalline form of lopinavir does not contain more than about 10% of any other compound, and in particular does not contain more than about 10% of any other form of lopinavir such as amorphous, solvated forms, unsolvated forms and desolvated forms. More preferably, the term substantially pure refers to a crystalline form of lopinavir which is more than about 95% pure. That is, the crystalline form of lopinavir does not contain more than about 5% of any other compound, and in particular does not contain more than about 5% of any form of lopinavir such as amorphous, solvated forms, unsolvated forms and desolvated forms. More preferably, the term substantially pure refers to a crystalline form of lopinavir which is more than about 97% pure. That is, the crystalline form of lopinavir does not contain more than about 3% of any other compound, and in particular does not contain more than about 3% of any other form of lopinavir such as amorphous, solvated forms, unsolvated forms and desolvated forms.

More preferably, however, the term substantially pure refers to a crystalline form of lopinavir which is more than about 98% pure. That is, the crystalline form of lopinavir does not contain more than about 2% of any other compound, and in particular does not contain more than about 2% of any other form of lopinavir such as amorphous, solvated forms, unsolvated forms and desolvated forms.

Most preferably, the term substantially pure refers to a crystalline form of lopinavir which is more than about 99% pure. That is, the crystalline form of lopinavir does not contain more than about 1% of any other compound, and in particular does not contain more than about 1% of any other form of lopinavir such as amorphous, solvated forms, unsolvated forms and desolvated forms.

The X-ray diffraction analysis of the powdered samples was performed as follows. Samples for X-ray diffraction analysis were prepared by spreading the sample in powder (ground to a fine powder in a mortar with a dot, or for limited amounts with a glass microscope slide) in a thin layer on the sample holder and gently smoothing the sample with a glass slide. Samples were measured in one of three configurations: on a rotating sample holder, on a zero background quartz plate, or on a heated support pad (similar to a background minimized pad). X-ray diffraction was performed using an XDS 2000 θ / 0 diffractometer (Scintag; 2 kW X-ray tube, normal focus, either liquid nitrogen or Peltier cooled germanium solid state detector; 45 kV and 30-40 mA; X-ray source: Cu-Καΐ; range: 2.00 ° - 40.00 ° 2 Θ; scan rate: 0.5 ° or 2 ° / min), XRD-6000 diffractometer (Shimadzu; X-ray tube, fine focus, with Nal scintillation detector; 40 - 45 kV and 30 - 40 mA; X-ray source: Cu-Καΐ; range: 2.00 ° - 40.00 ° 2 Θ; scan rate: 2 ° / min) or 1-2 X-ray diffractometer (Nicolet; scintillation detector; 50 kV) and 30 - 40 mA; X-ray source: Cu-Καΐ; Range: 2.00 ° 40.00 ° 2 Θ; Scan rate: 2 ° / min. The relative humidity of the sample on a heated support pad can be controlled using a model RH200 generator. VTI Corp.).

The characteristic peak positions in the powder X-ray diffraction pattern are for the polymorphic modifications in the angular position data (2 Θ) with a tolerance of ± 0.1 °. This permissible variability is specified in U.S. Pat. Pharmacopeia str. 1,843-1,844 (1995). A deviation of ± 0.1 ° is intended for use when comparing two powder X-ray diffractograms. In practice, when a peak in the diffraction pattern of one type is assigned a range of angular positions (2 Θ) that is measured by a peak position of ± 0.1 ° and a peak in the diffraction pattern of another type is assigned a range of angular positions (2 0) 0.1 ° and if these ranges overlap, the two peaks are considered to have the same angular position (2 °). For example, if a peak in a diffraction pattern of one type is found to have a peak position of 5.20 °, for purposes of comparison, the permissible variability allows a peak position within the range of 5.10 ° to 5.30 °. If the compared peak in the diffraction pattern of another type is found to have a peak position of 5.35 °, the permissible variability allows for a peak position in the range of 5.25 ° - 5.45 ° for comparison purposes. Because there is an overlap between the two peak position ranges (i.e., 5.10 ° - 5.30 ° and 5.25 ° - 5.45 °) when the two peaks are compared, they are considered to have the same angular position (2 Θ).

Solid state analysis by nuclear magnetic resonance was performed as follows. The Bruker AMX-400 instrument was used with the following parameters: CP-MAS (magic angle rotation by transverse polarization); the spectrometer frequency for ¹³ C was 100.6 MHz; the pulse sequence was VA-CP2LEV; the contact time was 2.5 milliseconds, the dirt rate was 7000 Hz; the recycle delay time was 5.0 seconds; number of scans 3,000).

Analysis of the samples using the near-infrared FT spectrum was performed as follows. Samples were analyzed as pure, undiluted powders contained in transparent glass vials having 1 µm (~ 3.7 mL). The Nicolet Magna System 750 spectrometer was used with Nicolet Sabl® accessories, near IR infrared reflectance fiber optic probes; the detector was PbS; CaF ₂ ray cleavage; number of sample readings 16; the resolution was 8 cm ¹ .

The analysis of samples using the FT spectrum of the middle infrared region was performed as follows. The samples were analyzed as pure, non-inherited powders. A Nicolet Magna System 750 spectrometer was used with a Nicolet NIC-PLAN microscope with a liquid nitrogen cooled MCT-A detector. The sample was placed on a sample holder of a BaF ₂ 13 x 1 mm disc; , at 4 ^cm-1 was scanned display 64.

The analysis of samples by differential scanning calorimetry was performed as follows. Differential Scanning Calorimeter T. A. Instruments Model 2920 with T. A. Instruments DSC Data Analysis Cell with Thermal Solution version 2.3. The analysis parameters were: sample size: 4-10 mg, placed in an aluminum pan and sealed after pin-hole piercing; heating rate: 1 ° C / min with dry nitrogen purge (40-50 mL / min).

Thermogravimetry was performed by heating the sample at 1 ° C or 5 ° C per minute from ambient temperature to 200 ° C.

The foregoing is illustrative only for the invention and is not intended to be limited to the disclosed embodiments. Variations and changes that will be apparent to those skilled in the art are deemed to correspond to the scope and nature of the invention as defined in the appended claims.

Claims (23)

PATENT CLAIMS A crystalline hydrated form of lopinavir. 2. The crystalline form of lopinavir claim 1, which is in the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1652-1666 cm ¹ and the maximum of the absorption band in the infrared spectrum of the solid state at a position in the range of 1606-1615 cm ¹ . 3. A substantially pure crystalline hydrated form of lopinavir. The crystalline form of lopinavir according to claim 3, having a maximum absorption band in the infrared spectrum of the solid state at a position in the range of 1,652 - 1,666 cm ^-1 and a maximum absorption band in the infrared spectrum of the solid state at a position in the range of 606 - 1,615 cm ' ¹ . 5. A solvated crystalline form of lopinavir having a maximum absorption band in the infrared spectrum of the solid state at 1,661-1,673 cm ^-1 , a maximum absorption band in the infrared spectrum of the solid state at 1,645-1,663 cm ^-1 and a maximum absorption band in the solid state infrared spectrum at a position in the range of 1,619-1,629 cm ^-1 . 6. A substantially pure solvated crystalline form of lopinavir having a maximum absorption band in the solid state infrared spectrum at a position in the range of 1,661 - 1,673 cm ^-1 , a maximum absorption band in the solid infrared spectrum at a position in the range of 1,645 - 1,653 cm @ ^-1 and the maximum absorption band in the solid state infrared spectrum at a position in the range of 1,619 - 1,629 cm @ ^-1 . 7. A crystalline form of lopinavir which has a maximum absorption band in the infrared spectrum of the solid state at a position between 1,655-1,662 8. A crystalline form of lopinavir, which is in the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1655-1662 cm ^"1, and the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1636-1647 ^cm-first 9. A substantially pure crystalline form of lopinavir having a maximum absorption band in the infrared spectrum of the solid state at a position ranging from 1,655-1,662 cm ^-1 . 10. The substantially pure crystalline form of lopinavir, which is in the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1655-1662 cm ¹ and the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1 636- 1 647 ^cm-1 . 11. A solvated crystalline form of lopinavir having a maximum absorption band in the infrared spectrum of the solid state at a position ranging from 1,655 to 1,662 cm ^-1 ; 12. A solvated crystalline form of lopinavir having a maximum absorption band in the infrared spectrum of the solid state at a position within the range of 1655-1662 cm ^-1 and in the infrared spectrum of the solid state the maximum absorption band at a position in the range 1626-1647 cm ^-1 . 13. The substantially pure crystalline form of lopinavir solvate having an infrared spectrum of the solid state the maximum absorption band at a position in the range of 1 655- 1 662 ^cm-first 14. A substantially pure solvated crystalline form of lopinavir which has a maximum absorption band at 1655-1622 cm ^-1 in the solid state infrared spectrum and a maximum absorption band at 1626-1647 cm in the infrared spectrum. ' ¹ . 15. The unsolvated crystalline form of lopinavir. 16. The crystalline form of claim 15 lopinavir, which is in the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1 680- 1 685 ^cm-1 IR spectrum and solid state absorption band maximum at a position in the range of 1625-1630 cm " ¹ . The crystalline form of lopinavir according to claim 15, which has characteristic peaks at two aunt values of 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 12.88 ° ± 0.1 in the powder X-ray diffraction pattern. °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 ° and 18.53 ° ± 0.1 °. The crystalline form of lopinavir according to claim 15, which has characteristic peaks in the two-ate powder X-ray diffraction pattern 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. A substantially pure unsolvated crystalline form of lopinavir. 20. The crystalline form of claim 19 lopinavir, which is in the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1 680- 1 685 cm ^1, and the infrared spectrum of the solid state the maximum absorption band at a position in the range of 1625-1630 cm ^1st The crystalline form of lopinavir according to claim 19, which has a maximum absorption band at the 1680-1685 cm- ¹ position in the solid-state infrared spectrum and a maximum absorption band at the 1668-1674-cm position in the solid-state infrared spectrum. ¹ , in the infrared spectrum of the maximum absorption band at a position in the range of 1,656-1,662 cm ¹ , in the infrared spectrum of the maximum absorption band at a position in the range of 1,642 - 1,648 cm ^-1 , and in the infrared spectrum of the solid state at a position within the range 1 625 - 1 630 cm ^-1 . The crystalline form of lopinavir according to claim 19, which has characteristic peaks in the two-ate powder X-ray diffraction pattern 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 °. The crystalline form of lopinavir according to claim 19, which has characteristic peaks in a powder X-ray diffraction pattern at two ata 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 °.