SK163299A3 - Sulfate salt of n-(2(r)-hydroxy-1(s)-indanyl)-2(r)-phenylmethyl- 4-(s)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(s)-n'-(terc- butylcarboxamide)piperazinyl))pentanamide in a crystalline form, pharmaceutical composition containing the same and use thereof - Google Patents

Abstract

This invention relates to a sulfate salt of an HIV protease inhibitor, Compound (A), which is useful in the treatment of AIDS, ARC or HIV infection in adults and children. More specifically, the invention provides a sulfate salt of the HIV protease inhibitor, Compound (A) having substantially improved solibility in dilute HC1 (gastric acid) solution which results in much greater oral absorption and bioavailability in animal models. Processes for making the sulfate salt of the particular HIV protease inhibitor compounds are also disclosed.

Description

N - (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4 (2-benzo [2-benzo [2,3-d]) [ b] furanylmethyl) -2 (S) - N - (tert-butylcarboxamido) piperazinyl)) pentanamide in crystalline form, process for its preparation, pharmaceutical composition containing it and its use

Technical field

The present invention provides a pharmaceutically acceptable sulfate salt and a process for producing an HIV protease inhibitor. More specifically, the invention provides the HIV protease inhibitor sulfate compound, Compound A, which has substantially improved solubility in dilute HCl solution (gastric juice), resulting in much higher absorption after oral administration and much higher bioavailability in animal models.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus is the etiological agent of a complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degenerative diseases of the central and peripheral nervous systems. Recently, a number of HIV protease inhibitor compounds have been found to be useful in the treatment of HIV infection and in the treatment of AIDS. These HIV protease inhibiting compounds and their use in the treatment of HIV infection and AIDS are described in PCT International Application Publication WO 95/16688, published June 22, 1995. More specifically, the compound (R) - (2 (R) -hydroxy-1 (S)). ) indanyl) -2 (R) phenylmethyl-4 (S) -hydroxy-5- (1- (4- (2-benzo [b] furanylmethyl) -2 (S) - / V- (tert-butyl-carboxamido) -piperazinyl III) The pentanamide described in Example 3 of WO 95/16688 and referred to herein as Compound A is a potent HIV protease inhibitor and is useful in the treatment of AIDS or ARC (complex of AIDS-related diseases) without significant side effects or toxicity.

Compound A

Compound A is produced by the method of Example 3 of WO 95/16688 or by the methods detailed herein. Compound A has been identified as an HIV protease inhibitor suitable for the treatment of AIDS according to the methods described in WO 95/16688.

The preparation of an acceptable salt of compound A suitable for pharmaceutical purposes has proven to be problematic. Numerous attempts to isolate the crystalline salt form of Compound A have failed. Alternatively, the problem of a pharmaceutically acceptable salt for the HIV protease inhibitor compound A was solved by synthesis of the HCl (dihydrate) salt. However, the HCl (dihydrate) salt had low solubility in dilute HCl (gastric juice), resulting in poor absorption after oral administration in animal models. In addition, HCl (dihydrate) is extremely hydrophobic in nature, requiring the addition of wetting agents during manufacture to achieve an acceptable dispersion that increases the size of the solid dosage form or number of tablets required to achieve the desired dosage, as well as the complexity and cost of manufacture, all undesirable. These problems have been solved by identifying a pharmaceutically acceptable sulfate salt of Compound A of the present invention. More specifically, the sulfate salt of the present invention has substantially improved solubility in dilute HCl solution (gastric juice), resulting in much higher absorption after oral administration and improved bioavailability in animal models. In addition, the sulfate salt of Compound A is easy to produce compared to the HCl salt because of its hydrophilic nature.

3. Summary of the Invention

The present invention provides the N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4- (2) -) -benzo [b] furanylmethyl) -2 (S) - N- (tert-butylcarboxamido) piperazinyl) pentanamide of the formula

and solvates thereof.

In another embodiment of the invention, the compound is

in crystalline form.

Preferably, the compound is crystalline sulfate of compound A.

In the subgroup of the invention, the compound is characterized by a differential imaging calorimetry (DSC) curve at a heating rate of 10 ° C / min in an open dish under nitrogen flow representing an endotherm with an extrapolated onset of about 190 ° C, a peak temperature of about 193 ° C and an associated heat of about 120 J / gm.

Illustratively according to the invention, the compound is characterized by powder X-ray diffraction with d-spacings of 11.72, 5.56, 5.20, 5.00, 4.60, 4.50, 4.40, 4.26,

4.17, 4.08, 3.90, 3.81, 3.69, 3.24 and 3.33

The invention also encompasses a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the invention is made by combining any of the compounds mentioned above and a pharmaceutically acceptable carrier.

The invention also provides a method of making a pharmaceutical composition by combining any of the compounds mentioned above and a pharmaceutically acceptable carrier.

Further, the invention provides any of the compounds of the invention for use in inhibiting HIV protease, treating and / or preventing HIV infection and treating or preventing AIDS.

The invention further provides the use of any of the compounds described above for the manufacture of a medicament for: a) inhibiting HIV protease; b) treating or preventing HIV protease infection; c) treating or preventing AIDS; in a patient with an indication of such treatment.

The invention also provides a process for preparing a compound of formula

H ₂ SO ₄ and solvates thereof, comprising the steps of:

(a) dissolving the free base of a compound of formula

II

-5 in a solvent to form a solution; and (b) treating the solution of step (a) with sulfuric acid to form a compound of formula

Another embodiment of the invention is a production method wherein the compound of formula

it is in crystalline form.

In the process of the invention, the solvent is selected from ethanol, ethyl acetate or isopropyl acetate.

A preferred embodiment of the invention is a process for preparing a compound of formula

which includes the steps of:

-6 (a) dissolving the free base of a compound of formula

in ethanol to form a solution; and (b) treating the solution of step (a) with a solution of sulfuric acid in ethanol to form a compound of formula

Preferably, the sulfate salt of compound A is in crystalline form.

In an even more preferred embodiment of the process of the invention, the compound produced in step (b) is isolated at a temperature between about 15 to 25 ° C.

In a more preferred embodiment of the process of the invention, the sulfuric acid in the ethanol solution of step (b) is maintained at a temperature below + 5 ° C during the addition.

In another embodiment of the invention, the compound is produced by a method comprising:

(a) dissolving the free base of a compound of formula

in ethanol to form a solution; and (b) treating the solution of step (a) with a solution of sulfuric acid in ethanol to form a compound. Preferably, the compound is isolated at a temperature between about 15 to about 25 ° C and the sulfuric acid in the ethanol solution of step (b) is maintained at a temperature below + 5 ° C during the addition.

The present invention provides pharmaceutically preferred salts of an effective HIV protease inhibitor, Compound A, pharmaceutical compositions containing them, and methods of making and using the pharmaceutically preferred salts of Compound A. The sulfate salts of Compound A and the pharmaceutical compositions of the present invention are useful in inhibiting HIV protease. and / or treating an infection caused by human immunodeficiency virus (HIV) and in preventing and / or treating subsequent pathological conditions such as AIDS in adults, children or toddlers. Treatment of AIDS or the prevention or treatment of HIV infection includes, but is not limited to, the treatment of a wide variety of stages of HIV infection: AIDS, ARC (complex of AIDS-related diseases) both symptomatic and asymptomatic and actual or potential exposure to HIV. For example, the salts and pharmaceutical compositions of the invention are useful in the treatment of HIV infection upon suspected prior exposure to HIV, e.g. in blood transfusion, body fluid exchange, bites, accidental needle puncture, or patient exposure to blood during surgery.

The term "compound A" as used herein includes the free base listed below:

Compound A and its ability to inhibit HIV protease and the ability to treat and / or prevent AIDS is described in detail in WO 95/16688. Compound A is readily obtainable by the method of Example 3 of WO 95/16688, or by the methods described herein, starting from the penultimate intermediate of Compound 6.

(6)

Compound 6 is produced by known methods, for example, the methods described in US Patent No. 5,201,549. 5,618,937 (see, e.g., Examples 1 to 27).

The invention encompasses the production of a pharmaceutically acceptable sulfate salt of the HIV protease inhibitor, Compound A, by treating the free base dissolved in the solvent with sulfuric acid. In particular, the free base of compound A is dissolved in a solvent and treated with about 1.0 to about 1.1 equivalents of sulfuric acid at a temperature of about 0 to 40 ° C to form the sulfate salt of compound A. If desired, sulfuric acid can be added as a solution of sulfuric acid in a solvent. Preferably, about 1.0 equivalents of sulfuric acid is added to a solution of the free base of Compound A in a solvent at a temperature of about 10 to 30 ° C, ideally the sulfate of Compound A is isolated at a temperature between about 15 and about 25 ° C.

A wide variety of solvents can be used as long as the free base of Compound A is soluble in the solvent. Therefore, suitable solvents include but are not limited to water or water-containing esters, amides, ethers, alcohols and hydrocarbons. Preferably, water-containing esters, alcohols or ethers are used as the solvent; more preferably water-containing alcohols or esters; most preferably, ethanol, ethyl acetate or isopropyl acetate are used as the solvent. In a most preferred embodiment, ethanol is used as the solvent to produce the sulfate salt of compound A.

Thus, according to one embodiment, the invention comprises forming a pharmaceutically acceptable sulfate salt of the HIV protease inhibitor Compound A by treating the free base in ethanol at a temperature between about 0 to 25 ° C (preferably at room temperature) with sulfuric acid in ethanol solution maintained at about - 5 ° C to + 5 ° C followed by crystallization. The resulting sulfate salt is isolated as the crystalline sulfate salt of compound A. Preferably, the crystalline sulfate salt of compound A is isolated at a temperature between about 15 to 25 ° C. Other sulfate solvates are also available by this process using solvents already described in place of ethanol. The sulfate salt has the desired pharmaceutical properties and is more rapidly absorbed as existing HCl, HBr, and the methanesulfonate salt.

The term "individual" as used herein includes an animal, preferably a mammal, most preferably a human being treated, monitored or tested.

The term "therapeutically effective amount" as used herein means the amount of active compound or pharmaceutical active ingredient that elicits a biological or medical response in a tissue, system, animal or human such as a researcher, veterinarian, general practitioner or other clinic expects. , which includes alleviating the symptoms of the disease being treated.

As used herein, the term "preparation" refers to a product containing specific components in specific amounts, as well as any product that results directly or indirectly from the combination of specific components in specified amounts.

The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of this invention that are readily convertible in vivo to the desired compound.

Thus, in the methods of treatment of the present invention, the term "administration" is intended to include treatment of various diseases described by a specifically found compound or a compound that cannot be specifically discovered, but which converts to a specific compound in vivo upon administration to a patient. Conventional procedures for the selection and production of suitable prodrug derivatives are described e.g. in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species resulting from the introduction of the compounds of this invention into the biological environment.

In general, the compounds of the present invention include Compound A as the sulfate salt. In a preferred embodiment, the sulfate salt of Compound A is in crystalline form. A preferred compound is the sulfate salt of Compound A enolate in crystalline form, and even more preferred is the sulfate salt of Compound A monoelonate in crystalline form.

The compounds of the present invention are useful for inhibiting HIV protease, preventing or treating human immunodeficiency virus (HIV) infection, and for treating subsequent pathological conditions such as e.g. AIDS. Treatment of AIDS or the prevention or treatment of HIV infection includes but is not limited to the treatment of a wide variety of stages of HIV infection: AIDS, ARC (complex of AIDS-related diseases), both symptomatic and asymptomatic and actual or potential exposure to HIV. E.g. the compounds of the invention are useful in the treatment of HIV infection upon suspected previous exposure to HIV, e.g. in blood transfusion, organ transplantation, body fluid exchange, bites, accidental needle puncture, or patient exposure to blood during surgery.

For these reasons, the compounds of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injections or infusions), by inhalation sprays, or rectally, in single dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

Therefore, according to the present invention there is further provided a method of treatment and a pharmaceutical composition for the treatment of HIV infection and AIDS. The treatment comprises administering a pharmaceutical composition comprising a pharmaceutical carrier and therapeutically effective

An amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient indicating such treatment.

These pharmaceutical preparations may be in the form of orally administrable suspensions or tablets; nasal sprays; sterile injectable preparations, e.g. sterile injectable aqueous or oily suspensions or suppositories.

For oral administration in the form of a suspension, such formulations are prepared according to procedures well known to those skilled in the pharmaceutical art and may contain microcrystalline cellulose for volume adjustment, alginic acid or sodium alginate as suspending agent, methylcellulose to increase viscosity and sweetening / flavoring agents also well known. As instant dissolving tablets, these preparations may contain microcrystalline cellulose, calcium phosphate, starch, magnesium stearate and lactose, and / or other excipients, binders, fillers, disintegrants, diluents and humectants known in the art.

For nasal aerosol or inhalation administration, these formulations are prepared according to procedures well known to those skilled in the art of pharmaceutical manufacture and can be made as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and and / or other solubilizing or dispersing agents known in the art.

Injectable solutions or suspensions may be prepared in a manner known in the art using suitable non-toxic parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution or suitable dispersing or wetting and suspending agents such as sterile , non - irritating, fixed oils, including mono- or

I di-glycerides and fatty acids, including oleic acid.

For rectal suppository administration, these preparations can be made by mixing the drug with a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols that are solids at normal temperatures but become liquid and / or dissolve in the rectal cavity, to release the drug.

Dosage amounts in the order of 0.02 to 5.0 or 10.0 g / day are useful in the treatment or prevention of the aforementioned diseases, wherein the oral doses are

-12- two to five times higher. E.g. HIV infection is treated effectively at doses of 1.0 to 50 mg of compound / kg body weight 1 to 4 times daily. In one preferred dosage regimen, each patient is dosed from 100 to 400 mg every 6 hours orally. It is understood, however, that the specific dose and frequency of administration may vary from patient to patient and will depend on a number of factors including the potency of the specific compound used, the metabolic stability and duration of action of each compound, age, body weight, general health, sex and time. administration, elimination rate, combination of drugs, severity of the particular condition and from the patient undergoing treatment.

The abbreviations used in the immediate specification, particularly in the schemes and examples, are as follows:

Aq = aqueous Ac = acetyl EtOH = ethanol IPAc = isopropyl acetate t-Bu = tertiary butyl

The following examples are provided to further illustrate the invention, but not to limit the invention to specific examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

NaBH (OAc) ₃ , CH ₃ COOH isopropyl acetate

20 ° C

A solution of IPAc / methanol (about 20% methanol in isopropyl acetate) containing the penultimate intermediate (70.7 L, 8.66 mol, 4.53 kg) is concentrated under vacuum (25-46 ° C, 100 mm Hg) 1) to about 20 L of constant volume with the addition of IPAc to effect a constant volume shift of solvent to IPAC from the methanol / IPAc mixture. A final volume of 44 L and a KF (Curry Fisher) titration for water of 994 mg / L were obtained. The NMR spectrum did not show any detectable methanol.

One portion of benzofuran-2-carboxaldehyde (1.49 kg, 9.70 mol) was added at 22-23 ° C and 500 mL of IPAc for washing. Sodium triacetoxyborohydride was added as a solid over 10-15 min (2.90 kg, 13.0 mol) in one portion at room temperature, followed by rinsing with 500 mL IPAc. Glacial acetic acid (495 mL) was added at 27-28 ° C and the mixture was allowed to stand for 2.5 h at 20-21 ° C. The reaction was quenched by addition of 8,113.8% KHCO ₃ aqueous solution, gas formation (hydrogen) was observed. The combined batch was added to the extractor and additional aqueous KHCO ₃ (16 L) and IPAc (15 L) was added. The mixture was stirred and the layers were separated and the IPAc phase was washed with additional aqueous KHCO ₃ solution (24 L), then washed 3 times with 24 L deionized water. The washed crude compound in the form of the free base solution of Compound A was then combined with a similar solution resulting from a parallel run at the same rate and the constant volume distillation of 52L was carried out at a pressure of 15 to 18 inches. (Hg) at 55 to 62 ° C to a final KF of 330 mg / L. The resulting thick sludge was cooled from 60 ° C to 3 ° C over 4 h and the solids were isolated using a 58.4 cm (23 inch) filter crucible; the cake was washed with cold 10 ° C IPAc (total 10 L and the wet solid was dried in a vacuum oven

-14 at 20 ° C; 25 to 28 in / Hg with nitrogen addition to obtain the free base of Compound A.

Example 2

Preparation of benzofuran-2-carbinol

A. Pd / C, H ₂ , MeOH

5 ° C to 22 ^e C

Method A

Benzofuran-2-carboxaldehyde (10.0 g, 68 mmol) was dissolved in methanol (90 mL). 5% Pd / C (0.500 g) was added and the reaction mixture was hydrogenated for 4.5 h at 40 psi H ₂ . The reaction was judged complete by tlc (4: 1 hexanes / ETOAc) and the solution was filtered to remove Pd / C and concentrated in vacuo to give benzofuran-2-carbinol as an oil.

Method B

Benzofuran-2-carboxaldehyde (10.0 g, 68 mmol) was dissolved in methanol (70 mL) and the solution was cooled to 5 ° C. Sodium borohydride (2.58 g, 68 mmol) was added portionwise at 5 ° C. The mixture was allowed to stand at 5 ° C for 40 min and allowed to warm to 1 ° C

room temperature (22 ° C). The reaction was considered complete with tlc (4: 1 hexanes / EtOAc) and the reaction mixture was cooled to 5 ° C. D1 water (20 mL) was added and the solution was concentrated in vacuo. EtoAc (80 mL) was added and the solution was washed with D1 water (2 x 20 mL). The EtOAc layer was concentrated in vacuo to give benzofuran-2-carbinol as an oil.

Example 3

Preparation of benzofuran-2-carbinol

== - OH, Pd (OAc) ₂

- * | || V-ch ₂ oh

_PPh3, CuI, n-BuNH ₂

2-lodophenol (500 mg, 2.27 mmol), propargyl alcohol (265 µL, 4.54 mmol), Pd / OAc ₁₂ (5.1 mg, 0.03 mmol), triphenylphosphine (12 mg, 0.046 mmol) n-Butylamine (450 µL, 4.5 mmol) and CuI (8.6 mg, 0.045 mmol) were combined in 4.5 mL THF and heated to 40 ° C under nitrogen for 36 h. The mixture was cooled to room temperature and the solvents were removed in vacuo and the residue was purified by SiO ₂ column chromatography on 100 g silica gel, eluting with 20% ethyl acetate in hexanes. Concentration of the product fractions gave 2- (hydroxymethyl) benzofuran. [Kudu, NG; Pal, M .; Mahanty, JS; Dasgupta, FK: JCS Chem. Com., 1992, 41]

Example 4

Preparation of 2-chloromethylbenzofuran

CH ₂ OH

SOCl ₂ , CH ₂ Cl ₂

5'Caž22'C

CH ₂ Cl

Method A

Benzofuran-2-carbinol (10.38 g, 68.4 mmol) was dissolved in methylene chloride (100 mL) and the solution was cooled to 5 ° C. Over 5 min was added thionyl chloride (5.49 ml, 75.2 mmol) and the reaction was allowed to stand at 5 ° C for 30 minutes and allowed to warm to 22 ^e C. The reaction mixture was left for 4 hours at 22 "C. . The methylene chloride portion was washed with DI water (4 x 60 mL) and filtered through silica gel. The solution was concentrated in vacuo to give a solid upon cooling. The crude product was dissolved in hexanes (120 mL) and treated with Darco G-60 (1.0 g). The slurry was filtered and the solution was concentrated in vacuo to give the 2-chloromethylbenzofuran compound as a solid.

-16Example 5

The isolated penultimate solid (13.1 g, 25 mmol) was mixed with IPAc (60 mL), water (20 mL), KHCO3 (4.25 g, 42.5 mmol), sodium iodide (1.88 g, 12 mL). , 5 mmol) and tetrabutylammonium bromide (600 mg, 1.86 mmol) and the mixture was heated to 45 ° C under a nitrogen atmosphere. 3- (Chloromethyl) benzofuran (4.6 g, 27.5 mmol) was added and the resulting mixture was heated to 59-61 ° C for 5 h. The mixture was left

Cool to room temperature and dilute with IPAc (100 mL) and separate the aqueous layer. The organic layer was washed with 3 x 50 mL water, then 50 mL brine and dried (MgSO 4, and the filtrate was concentrated in vacuo and washed with 100 mL IPAc and atmospheric concentrated to 80 mL, cooled to 25 ° C and allowed to stand. with stirring for 2 h. The solids were filtered and washed with cold IPAc (2 x 15 mL) to give compound A as the free base.

The free base of Compound A (25 g, 38.3 mmol) was dissolved in absolute ethanol (150 mL) at 22 ° C. The batch was filtered through a pm filter and the filter was washed with absolute ethanol (50 mL). Sulfuric acid / ethanol solution was made at a temperature below 5 ° C by adding concentrated sulfuric acid (3.91 g, 38.3 mmol) to a cooled solution (<5 ° C) of absolute ethanol (50 mL) at a rate such that the temperature remained <5 ° C. A portion of the acid solution (10 mL, 20% v / v) was added to the batch of compound A at 22 ° C. The dose of Compound A may or may not be inoculated with Compound A.Sulfate (500 mg) at 22 ° C at this point. Ideally, the dose of Compound A was inoculated since inoculation facilitates supersaturation throughout

I crystallization. The slurry was aged at 20-25 ° C for 30 min. The remainder of the acid solution was added via cannula for more than 60 min. The batch temperature remained between 20 and 25 ° C during the addition (caution: the acid solution was maintained at <5 ° C). The final thick sludge was allowed to stand at 20-25 ° C for 60 min and was filtered. The cake was washed with absolute ethanol (2 x 25 mL) and was dried under vacuum (25 ° Hg, 20 ° C) for 18 h with nitrogen evolution to produce sulfate of Compound A. The sulfate was characterized by a different imaging curve Calorimetry (DSC), at a heating rate of 10 ° C / min in an open dish under nitrogen flow representing

-18endotherm with an extrapolated onset temperature of about 190 ° C, a peak temperature of about 193 ° C, and a related heat of about 120 J / gm. Based on TG and TG-FTIR results, the endotherm is caused by a combination of ethanol loss and melting with decomposition. The X-ray diffraction pattern of the powder sample is characterized by d-spacings of 11.72, 5.56, 5.00, 4.60, 4.50, 4.40, 4.26, 4.17, 4.08, 3.90, 3. , 81, 3.69, 3.24, and 3.33 °.

Example 7

As a specific example of an oral formulation, 100 mg of the compound of Example 6 is treated with a sufficiently fine amount of lactose to give a total amount of 580 to 590 mg to be filled into an O solid gelatin capsule.

Since the foregoing specification explains the principles of the present invention, it will be understood from the illustrative examples that the practice of the invention allows all conventional variations, adaptations, modifications, omissions or additions to the procedures and guidance provided herein, which is within the scope of the following claims and their equivalents.

Claims (12)

PATENT CLAIMS N - (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4- (2-benzo [b] furanylmethyl) sulfate) salt (-2) (N- (tert-butylcarboxamido) piperazinyl)) pentanamide in crystalline form of the formula wherein the compound in crystalline form has (i) a differential imaging calorimetry (DSC) curve at a heating rate of 10 ° C / min on an open dish a nitrogen flow representing an endotherm with an extrapolated onset of about 190 ° C, a peak temperature of about 193 ° C and an associated heat of about 120 J / gm; and (ii) powder X-ray diffraction with d-spacings of 11.72, 5.56, 5.20, 5 , 00, 4.60, 4.50, 4.40, 4.26, 4.17, 4.08, 3.90, 3.81, 3.69, 3.24 and 3.33 A. A process for producing a compound according to claim 1, comprising: a) dissolving the free base of the compound of formula in a solvent to form a solution; and b) treating the solution of step a) with sulfuric acid to form the compound in crystalline form. 3. A process according to claim 2 wherein the solvent is selected from ethanol, ethyl acetate or isopropyl acetate. 4. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition which is produced by admixing a compound of claim 1 with a pharmaceutically acceptable carrier. 6. A process for the manufacture of a pharmaceutical composition comprising admixing a crystalline form of a compound of claim 1 and a pharmaceutically acceptable carrier. The compound of claim 1 for use in the treatment of HIV infection. A compound according to claim 1 for use in the treatment of AIDS. A compound according to claim 1 for use in inhibiting HIV protease. A pharmaceutical composition according to claim 4 or 5 for the treatment of HIV infection. -21 Pharmaceutical composition according to claim 4 or 5 for the treatment of AIDS. A pharmaceutical composition according to claim 4 or 5 for inhibiting HIV protease.