DE112010004862T5 - Polymorphic form of nevirapine and its preparation - Google Patents

Abstract

The invention relates to a metastable unsolvated crystalline form (form IV) of nevirapine, comprising at least one characteristic X-ray diffraction peak at approximately 7.1 ° to 7.5 ° two-theta. The invention further relates to a manufacturing method for manufacturing a particulate unsolvated form of nevirapine.

Description

Introduction and background of the invention

The invention relates to a novel polymorphic form of a composition. In particular, the invention relates to a novel polymorphic form (Form-IV) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] - [1, 4] -diazepin-6-one or nevirapine. The invention further relates to a process for the preparation of a particulate anhydrous unsolvated form of nevirapine.

Nevirapine is a well-known antiretroviral drug used to treat HIV-1 infections (human immunodeficiency virus type 1) and AIDS. It is a non-nucleoside reverse transcriptase inhibitor that specifically inhibits HIV-1 reverse transcriptase. Structurally, nevirapine is a member of the dipyridodiazepinone chemical class of compounds.

Currently, nevirapine is available in two dosage forms, namely as tablets (anhydrous form) and as suspensions (hemi or hemihydrate). The average particle sizes of commercial nevirapine are generally greater than 50 microns and typically 125 microns.

Anhydrous nevirapine refers to the known unsolvated / unhydrated form of nevirapine, which is currently commercially available and in which U.S. Patent 5,366,972 is described. For the purposes of this application, this form is referred to as the original polymorphic "Form I" of nevirapine. The crystalline form II and form III of nevirapine are described in the two US patent applications US 2005/0059653 A1 and US 2006/0183738 A1.

A first disadvantage associated with the preparation of commercial unsolvated / unhydrated nevirapine (Form-I) is that the average particle size of the base material is relatively large. As a result, the base material must be crushed or ground to obtain the preferred particle size which allows handling and processing. Usually, this means a reduction of the average particle size to 125 μm or less.

A disadvantage associated with the crushing or grinding process is that the process generates heat which can adversely affect heat sensitive materials. Another disadvantage is that the process increases the number of high energy sites in the solid nevirapine particles, and this factor can adversely affect the stability of the nevirapine end product.

Another disadvantage of the crushing or grinding process is that the investment, set-up, maintenance and operating costs are relatively high.

Moreover, another disadvantage of the crushing or grinding process is that very fine particulate nevirapine is partially lost during the process, which both reduces the yield and creates an excess of dust in the plant.

Moreover, another disadvantage of the crushing or milling process is that the particle size distribution of the crushed or ground nevirapine varies over a relatively wide range, which adversely affects the pourability, flowability and behavior of the substance in the handling and preparation of dosage forms.

Objects of the invention

An object of the present invention is to provide a novel form (Form-IV) of nevirapine. Another object of the invention is to provide a process for producing a particulate anhydrous unsolvated form of nevirapine (Form-I). In addition, an object of the invention is to provide a medicament which is produced by such a method and with which the disadvantages described above can be overcome or at least reduced.

Summary of the invention

According to the first aspect of the invention, there is provided a composition comprising a metastable unsolvated crystalline form (Form-IV) of nevirapine.

The metastable unsolvated crystalline form (Form-IV) of nevirapine may have an X-ray powder diffraction pattern which has at least one characteristic peak at about 7.1 ° to 7.5 ° 2-theta.

The nevirapine metastable unsolvated crystalline form (Form-IV) may show differential scanning calorimetry (DSC) an exothermic phase transition with an onset temperature in the range of 70 degrees Celsius to 100 degrees Celsius.

The metastable unsolvated crystalline form (Form IV) of nevirapine may have a as in 2 shown derivative Thermogravimetrie trace or curve with a weight loss of less than 2% before reaching 200 degrees Celsius show or have.

Furthermore, according to the invention, the metastable unsolvated crystalline form (Form IV) of nevirapine may have an X-ray diffraction pattern, based on the crystal structure, of 7.14, 11.37, 12.19, 13.05, 13.92, 14.31, 15 , 18, 18.50, 18.96, 19.15, 19.86, 20.45, 21.50, 22.65, 23.03, 23.53, 23.83, 24.43, 24.73 , 25.20, 25.91, 26.99, 27.59, 28.04, 28.86, 32.25, 35.09, 36.18, 37.00, 37.40, 38.46, 38 , 80 ± 2 degrees 2-theta.

Furthermore, according to the invention, the metastable unsolvated crystalline form (Form-IV) of nevirapine can show an experimental X-ray diffraction pattern: 7.52, 11.71, 12.65, 13.49, 14.29, 14.61, 15.49, 17, 22, 17, 18, 20, 17, 21.78 46, 26.01, 26.92, 27.36, 27.90, 28.54, 28.96, 29.28, 30.17, 31.25, 32.64, 33.35, 34.09, 34.35, 34.80, 35.62, 36.34, 37.17, 37.75, 38.55 degrees 2-theta.

The metastable unsolvated crystalline form (Form-IV) of nevirapine may be in particulate form and the particles may have an average maximum diameter of less than 125 μm.

• – Herstellen einer Lösung von wasserfreiem unsolvatisiertem Nevirapin (Form-I) in einem Lösemittel;
• – Verringern bzw. Reduzieren der Temperatur der Lösung, um das gelöste Nevirapin als eine metastabile unsolvatisierte kristalline Form (Form-IV) von Nevirapin zu kristallisieren;
• – Abtrennen der metastabilen unsolvatisierten kristallinen Form (Form-IV) von Nevirapin von dem Lösemittel; und
• – Übergehenlassen der metastabilen unsolvatisierten kristallinen Form (Form-IV) von Nevirapin zu partikulärem wasserfreiem unsolvatisiertem Nevirapin (Form-I).

According to a second aspect of the invention there is provided a process for the preparation of a particulate anhydrous unsolvated form of nevirapine (Form-I) comprising the steps of:

• Preparing a solution of anhydrous unsolvated nevirapine (Form I) in a solvent;
• Reducing or reducing the temperature of the solution to crystallize the dissolved nevirapine as a metastable unsolvated crystalline form (Form-IV) of nevirapine;
• Separating the metastable unsolvated crystalline form (Form-IV) from nevirapine from the solvent; and
• - passing the metastable unsolvated crystalline form (Form-IV) of Nevirapine to particulate anhydrous unsolvated Nevirapine (Form-I).

Furthermore, according to the invention, the solvent may be in the form of methanol.

The maximum mean diameter of the transmitted particulate anhydrous unsolvated nevirapine that forms may be less than 125 μm.

Furthermore, according to the invention, the particle size distribution of the formed particulate anhydrous unsolvated nevirapine (Form-I) is in a relatively narrower range than that of the anhydrous unsolvated nevirapine (Form-I) which is subjected to comminution / grinding in accordance with prior art methods.

The step of preparing a solution of anhydrous unsolvated nevirapine (Form-I) in methanol may comprise the further step of raising the temperature of the methanol to within 10 degrees Celsius below the boiling point of methanol.

The step of reducing the temperature of the solution may include the step of reducing the temperature at a rate of at least 50 degrees Celsius per hour.

Alternatively, the step of reducing the temperature of the solution may include the step of stirring the solution while decreasing the temperature resulting in a metastable unsolvated crystalline form (Form-IV).

The step of separating the metastable unsolvated crystalline form (Form IV) from nevirapine from the solvent methanol may include the step of removing the methanol by stripping off the methanol from the nevirapine and allowing any residual methanol to evaporate.

The step of passing the metastable unsolvated crystalline form (Form-IV) to particulate anhydrous unsolvated nevirapine (Form-I) may comprise the step of spontaneously disintegrating the metastable unsolvated crystalline form (Form-IV) upon removal of the methanol to yield a powder to form a maximum average particle size of less than 125 microns.

According to a third aspect of the invention there is provided a particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable according to the second aspect of the invention.

According to a fourth aspect of the invention, there is provided a drug or drug which is prepared from the particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable by the method according to the second aspect of the invention.

According to a fifth aspect of the invention, there is provided the use of a pharmaceutically effective amount of a particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable by the method according to the second aspect of the invention in a method of treating a patient suffering from a condition of immune deficiency provided.

According to a sixth aspect of the invention, there is provided the use of a pharmaceutically effective amount of a particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable by the process according to the second aspect of the invention in a process for the manufacture of a medicament for use in the treatment of a provided to opportunistic diseases associated with conditions of immunodeficient patients.

According to a seventh aspect of the invention there is provided a method of treating a patient suffering from a condition of immunodeficiency, comprising the step of administering a pharmaceutically effective amount of the particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable by the method according to the second Aspect of the invention, to such a patient.

Furthermore, according to a further aspect of the invention, there is provided a medicament which, starting from the particulate anhydrous unsolvated form of nevirapine (Form-I) according to the method of the second aspect of the invention, together with at least one inert pharmaceutically acceptable carrier or diluent in dosage forms, selected from the group consisting of tablets; capsules; powders; Solutions; syrups; suspensions; bolus injections; continuous infusions; Powders for dissolution; Anoint; creams; gels; lotions; sprays; enemas; showers; pessaries; transdermal patches; dermal patches and lozenges or candies is made.

Brief description of the figures

The invention will now be further described, by way of example only, with reference to the accompanying drawings:

1 : is a DSC trace (differential scanning calorimetry or dynamic differential scanning calorimetry) of the metastable unsolvated crystalline form (Form-IV) of nevirapine according to an embodiment of the invention. DSC: Shimadzu DSC-60A (Japan) with the software TA60 Version 2.11. The samples were weighed in closed aluminum crucibles and heated. The samples were heated in an inert nitrogen atmosphere at 10 K / min. The DSC was calibrated with a known amount of indium (vertical axis: heat flux (mW); horizontal axis: temperature (degrees Celsius));

2 : is a DTG trace (derivative thermogravimetry) of the metastable unsolvated crystalline form (Form-IV) of nevirapine. TGA: Shimadzu DTG-60 (Japan) with the software TA60 Version 2.11. The samples were heated in open aluminum crucibles from 25 degrees Celsius to 300 degrees Celsius at 10 K / min. Nitrogen gas was used as the inert atmosphere (vertical axis (left): weight (mg); horizontal axis: temperature (degrees Celsius); vertical axis (right): microvolt (μV));

3 is a characteristic x-ray powder diffraction (XRPD) pattern of the metastable unsolvated crystalline form (Form-IV) of nevirapine (above) and of the Transition into the particulate anhydrous unsolvated form of nevirapine (Form-I) according to another aspect of the invention as a function of time at ambient temperature. The calculation is based on CuKα radiation, λ = 1.5418 Å (vertical axis: relative intensity, horizontal axis: 2-theta (degrees));

4 Figure 12 is a simulated XRPD pattern of the nevirapine metastable unsolvated crystalline form (Form-IV) calculated using the single crystal X-ray structure of the isostructural ethanol solvate with suppressed solvent contribution (vertical axis: relative intensity; horizontal axis: 2-theta) (Degree));

5 : is an experimental XRPD pattern of a sample of nevirapine metastable unsolvated crystalline form (Form-IV) (vertical axis: intensity (CPS); horizontal axis: 2-theta (degrees));

6 to 11 13: SEM (scanning electron microscope) images depicting the particulate anhydrous unsolvated form of nevirapine (Form-I) obtained by using the method according to a preferred embodiment of the invention (FIG. 10 and 11 ) is prepared with commercially available, vendor-supplied, base materials ( 6 to 9 ) to compare. ( 6 . 8th and 10 have a 1,000x magnification and 7 . 9 and 11 have a 4,000x magnification); and

12 Figure 4 shows a proposed bead-and-stick design and crystal structure vial model illustrating the metastable unsolvated crystalline form (Form-IV) of nevirapine, determined using the single crystal X-ray structure of the isostructural ethanol solvate with suppressed solvent contribution.

Description of preferred embodiments of the invention

According to a preferred embodiment of the invention there is provided a process for the preparation of a particulate anhydrous unsolvated form of nevirapine (Form-I).

The method comprises the steps of preparing a solution of conventional (prior art) anhydrous unsolvated nevirapine (Form-I) in a solvent in the form of methanol; Raising the temperature of the solution to 10 degrees Celsius below the boiling point of methanol; Reducing the temperature of the solution to crystallize the nevirapine in solution as a new metastable unsolvated crystalline form (form IV) of nevirapine; Separating the metastable unsolvated crystalline form (Form-IV) from nevirapine from the methanol; and passing the metastable unsolvated crystalline form (Form IV) from nevirapine to particulate anhydrous unsolvated nevirapine (Form I).

Further details of the aforementioned steps of the method according to the invention:

Prepare a solution of anhydrous unsolvated Nevirapine (Form I) in a solvent

The first step of the process, according to a preferred embodiment of the invention, is the preparation of a solution of conventional anhydrous unsolvated nevirapine (Form-I) in methanol. When preparing the solution, a saturated solution of nevirapine in methanol is prepared. The nevirapine is added to the methanol and the temperature is raised to temperatures within 10 degrees Celsius below the boiling point of methanol with continuous stirring (about 50 ml of methanol per 1 g of nevirapine).

The subsequent step of reducing the temperature of the solution comprises the step of rapidly reducing the temperature of the solution at a rate of at least 50 degrees Celsius per hour, either by freezing or placing the container in ice water, resulting in the crystallization of the nevirapine in the solution introduces a new metastable unsolvated crystalline form (Form-IV) of nevirapine.

Alternatively, the temperature of the solution may be reduced while the solution is being continuously stirred, resulting in the crystallization of nevirapine in the solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine.

Method of separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the solvent

According to a further step of the invention, the crystalline form IV of nevirapine is separated by removing the methanol from the solvent methanol. The methanol is removed by stripping off the nevirapine and allowing any residual methanol to evaporate.

Conversion of Crystalline Form-IV to Particulate Unsolvated Anhydrous Nevirapine (Form-I)

According to a further step of the invention, the crystalline Form-IV is spontaneously decomposed after removal (evaporation) of the methanol and converted into particulate anhydrous unsolvated Nevirapine (Form I) powder.

Further analyzes and results

Surprisingly, it has been found that the maximum mean particle size of the particulate anhydrous unsolvated nevirapine (Form I) powder that is formed is less than 125 microns (without a crumbing step) and that its particle size distribution is within a relatively narrower range than that of conventional anhydrous unsolvated nevirapine, which is subjected to crushing / grinding according to the prior art methods.

A DSC track (differential scanning calorimetry) ( 1 ), a DTG trace (derivative thermogravimetry) ( 2 ) and X-ray powder diffraction patterns ( 3 to 5 ) of the novel metastable unsolvated crystalline form (Form-IV) of nevirapine were obtained.

Out 1 It can be seen that Form-IV is not a solvate because the exotherm shows the transition to the particulate anhydrous unsolvated form of nevirapine (Form-I). The absence of a desolvation endotherm thus confirms that the structure is not a solvate.

2 corresponds to a superimposition of the DTA track (differential thermal analysis) (upper trace) and the TG trace (thermogravimetry) (lower trace) of the metastable unsolvated crystalline form (form IV) of nevirapine. Out 2 Thus, it can be seen that Form-IV is not a solvate because weight loss is minimal before the sample reaches 200 degrees Celsius.

Form-IV of nevirapine has been shown to be isostructural (having the same crystalline structure) as the primary alcohol solvate of nevirapine, however, no solvent was included in this structure. Nevirapine's metastable unsolvated crystalline form (IV) XRPD pattern has been found to approximate the typical XRPD pattern that is common to members of a series of nevirapine isostructural solvates containing the primary alcohols CH ₃ (CH ₂ ) _n OH with n = 1-7. These solvates crystallize in the triclinic crystal system.

The simulated XRPD pattern of the complete nevirapine core structure as found in ethanol solvate was calculated and the contribution of the entrapped ethanol molecules was provided assuming that the nevirapine metastable unsolvated crystalline form (Form-IV) was solvent-free suppressed. 12 shows the crystal structure of the metastable unsolvated crystalline form (Form-IV) of nevirapine. The cross section of the empty channel (s) has maximum and minimum linear dimensions of ~ 3.5 and ~ 5.1 Å, resulting in an unusually low crystal density which makes the structure unstable.

The new unsolvated crystalline form of nevirapine (Form-IV) is characterized by its X-ray diffraction pattern. The metastable unsolvated crystalline form (Form-IV) of nevirapine has at least one peak at ~7.1 ° to 7.5 ° 2-theta in unsolvated form. The 2-theta values and the percent intensity of the relevant peaks in the simulated and experimental x-ray powder diffraction pattern of the metastable unsolvated crystalline form (Form-IV) of nevirapine are shown in Tables 1 and 2. Table 1: Simulated XRPD data derived from the pattern based on the structure of the metastable unsolvated crystalline form (Form-IV) of nevirapine 2-theta (θ °) d-spacing / Å Relative intensity hkl indices of the main contribution to the diffraction peak 7.14 12.38 100 0 0 1 11.37 7.78 14.6 0 1 0 12.19 7.26 43.0 1 0 0 13.05 6.78 24.5 1 1 0 13.92 6.36 61.6 1 0 -1 14.31 6.19 38.3 0 0 2 15.18 5.84 6.5 1 1 -1 18.50 4.80 1.5 1 0 -2 18.96 4.68 3.6 1 1 2 19.15 4.63 4.2 0 1 -2; 1 0 2 19.86 4.47 12.6 1 1 -2 20.45 4.34 4.3 1 -1 -1 21,50 4.13 10.9 1 -1 1; 0 0 3 22.65 3.93 10.9 2 1 0 23,03 3.86 31.0 1 2 -1 23.53 3.78 11.0 1 -1 -2 23.83 3.73 8.4 2 1 -1 24.43 3.64 11.8 1 0 -3 24.73 3.60 2.8 1 1 3 25,20 3.53 6.7 1 0 3 25.91 3.44 2.6 0 2 2 26,99 3.30 10.1 2 1 -2 27.59 3.23 10.9 2 2 -1 28.04 3.18 3.6 2 0 -2 28.86 3.09 2.6 0 0 4 32.25 2.78 6.6 2 1 1; 2 0 -3 35.09 2.56 2.4 3 1 1 36.18 2.48 1.6 3 2 -1 37,00 2.43 4.2 2 -1 -3; 0 1 5 37,40 2.40 3.4 3 1 2; 2 0 -4 38.46 2.34 2.0 2 2 4 38,80 2.32 1.2 0 2 -4 Table 2: Experimental XRPD data of the metastable unsolvated crystalline form (Form-IV) of nevirapine 2-theta (θ °) d-spacing / Å Relative intensity 7.5189 11.75788 41.79 11.7092 11.7092 5.76 12.6461 12.6461 14.33 13.4883 13.4883 23.88 14.2898 6.19830 30.33 14.6115 6.06253 100.00 15.4933 5.71943 4.23 17.2158 5.15085 3.51 17.6817 5.01618 1.92 18.7954 4.72137 10.08 19.4778 4.55748 5.26 20.1344 4.41032 18.87 20.7768 4.27538 2.60 21.6357 4.10755 66.20 21.7546 4.08537 94.77 23.0671 3.85581 20.38 23.3387 3.81155 19.39 23.8531 3.73050 22.72 24.6373 3.61351 34.78 25.4578 3.49889 31.75 26.0094 3.42592 12.47 26.9186 3.31223 6.57 27.3636 3.25936 14.65 27.9018 3.19771 7.21 28.5402 3.12762 5.61 28.9647 3.08274 7.59 29.2828 3.04998 3.08 30.1710 2.96218 1.34 31.2502 2.86230 0.97 32.6353 2.74392 7.83 33.3518 33.3518 1.28 34.0901 2.63007 2.99 34.3494 2.61081 2.71 34.7973 2.57822 1.78 35.6240 2.52027 1.67 36.3375 2.47240 1.94 37.1712 2.41885 8.44 37.7496 2.38310 2.72 38.5473 2.33560 2.02

The simulated XRPD pattern ( 4 ) has peaks which are substantially in unison with those of the experimental XRPD pattern of Form-IV (FIG. 3 (above) and 5 ) stand. This match confirms the predicted structure of Form-IV.

Between the XRPD patterns according to 4 and 3 (above) and 5 For this reason, it has not been expected that a perfect match will result in all elementary cells having the same orientation relative to the incident X-ray radiation in a single crystal. In a powder, each crystallite has its own orientation relative to the incident beam of X-radiation. Instead of displaying individual points of deflected X-ray concentrations as for a single crystal, reflection halos or halos of the corresponding concentrations are displayed in XRPD patterns, making the analysis of the diffraction pattern relatively more complex.

When Form-IV is allowed to dry (under normal atmospheric conditions), it transforms into a particulate anhydrous unsolvated form of nevirapine (Form-I). The Scanning Electron Microscope (SEM) images ( 6 to 11 ) compare the particulate anhydrous unsolvated form of nevirapine (Form-I) prepared by use of the preferred method of the invention ( 10 and 11 ), with commercial base materials obtained from suppliers ( 6 to 9 ). Particle measurement was used to demonstrate the properties of particles of the obtained particulate anhydrous unsolvated form of nevirapine (Form-I) and to confirm compliance with the British Pharmacopoeia guidelines for "very fine powders"(<125 μm).

It is believed that the disadvantages of the prior art processes for preparing conventional anhydrous unsolvated nevirapine (Form-I) are mitigated by a method according to the invention for producing the particulate anhydrous unsolvated form of nevirapine (Form-I). In particular, no comminution or grinding and subsequent sieving of the formed particulate anhydrous unsolvated form of nevirapine (Form-I) is required after their formation. It has been found that the flowability of the formed particulate anhydrous unsolvated form of nevirapine (Form-I) is far superior to that of conventional anhydrous unsolvated nevirapine (Form-I). This is attributed to the shape of the particles that are formed and the narrow range of the particle size distribution.

A method according to the invention for forming a particulate unsolvated anhydrous form of nevirapine (Form-I) has been found to offer a relatively more favorable alternative to conventional methods and also provides a product which in many respects contrasts with conventional anhydrous unsolvated nevirapine (Formed I). I) is superior.

The particulate unsolvated anhydrous form of nevirapine (Form-I) is formulated for administration by any conventional route, and the invention includes within its scope pharmaceutical compositions comprising a particulate unsolvated anhydrous form of nevirapine (Form-I) and which are useful in the art Use in human or veterinary medicine are suitable.

The pharmaceutical compositions are provided for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient, and may also contain further active ingredients if necessary. The particulate unsolvated anhydrous form of nevirapine (Form-I) is typically prepared for oral, buccal, topical or parenteral administration.

Oral administration is the preferred dosage form, especially in the form of tablets and capsules. The pharmaceutical composition for oral administration is conveniently in the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional methods with compatible excipients. Compositions for buccal administration are in the form of conventionally prepared tablets or lozenges.

The particulate anhydrous form of nevirapine (Form-I) may be further prepared for parenteral administration by bolus injection or continuous infusion. Formulations of injections are provided in a simple dosage form in ampoules or in multi-dose containers with an added preservative. Furthermore, the compositions are in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and contain adjuvants such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient is in powder form for dissolution with a suitable vehicle.

The particulate unsolvated anhydrous form of nevirapine (Form-I) may further be formulated for topical dosage forms, such as ointments, creams, gels, lotions, powders, transdermal patches, dermal patches or sprays made in a conventional manner.

The particulate unsolvated anhydrous form of nevirapine (Form-I) is further prepared in rectal and vaginal compositions, such as suppositories or retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides.

For oral administration, a suitable daily dosage regimen of the particulate unsolvated anhydrous form of nevirapine (Form-I) presently is one to two doses at a total of 100 mg to 400 mg per day for adults and 2 to 7, depending on the condition of the patient mg per kilogram for children.

The particulate unsolvated anhydrous form of nevirapine (Form-I) prepared according to the method of the present invention may be formulated as a medicament and is used for a method of treating a patient suffering from a condition of immunodeficiency by administering a pharmaceutically effective amount Dependence on the condition of the patient from one to two doses with a total of 10 mg to 400 mg per day for adults and 2 mg to 7 mg per kilogram for children used on such a patient.

It is further believed that variations in detail regarding a method of making a medicament and medicament obtainable by such a method are possible in accordance with the present invention without departing from the scope of the appended claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 5366972 [0004]

Claims (21)

A composition comprising a metastable unsolvated crystalline form (Form-IV) of nevirapine. The composition of claim 1, wherein the nevirapine metastable unsolvated crystalline form (Form-IV) has an X-ray powder diffraction pattern with at least one characteristic peak at about 7.1 ° to 7.5 ° 2 theta. The composition of claim 1 or 2, wherein the metastable unsolvated crystalline form (Form-IV) of nevirapine in Differential Scanning Calorimetry (ESC) exhibits an exothermic phase transition with an onset temperature in the range between 70 degrees Celsius and 100 degrees Celsius. A composition according to any one of claims 1 to 3, wherein the metastable unsolvated crystalline form (Form-IV) of nevirapine is a as in 2 shown derivative Thermogravimetrie trace with less than 2% weight loss to 200 degrees Celsius shows. A composition according to any one of claims 1 to 4, wherein the nevirapine metastable unsolvated crystalline form (Form-IV) has a calculated X-ray diffraction pattern of 7.14, 11.37, 12.19, 13.05, 13.92, 14.31, 15,18, 18,50, 18,96, 19,15, 19,86, 20,45, 21,50, 22,65, 23,03, 23,53, 23,83, 24,43, 24, 73, 25,20, 25,91, 26,99, 27,59, 28,04, 28,86, 32,25, 35,09, 36,18, 37,00, 37,40, 38,46, 38.80 ± 2 degrees 2-theta. A composition according to claim 1 wherein the nevirapine metastable unsolvated crystalline form (Form-IV) has an experimental X-ray diffraction pattern of 7.52, 11.71, 12.65, 13.49, 14.29, 14.61, 15.49, 17, 22, 17, 18, 20, 17, 21.78 46, 26.01, 26.92, 27.36, 27.90, 28.54, 28.96, 29.28, 30.17, 31.25, 32.64, 33.35, 34.09, 34.35, 34.80, 35.62, 36.34, 37.17, 37.75, 38.55 degrees 2-theta. A composition according to any one of claims 1 to 6, wherein the metastable unsolvated crystalline form (Form-IV) of nevirapine is in particulate form and wherein the particles have an average maximum diameter of less than 125 μm. A composition according to any one of claims 1 to 7, having a crystal structure substantially as in 12 displayed. A process for producing a particulate anhydrous unsolvated form of nevirapine (Form-I) comprising the steps of preparing a solution of anhydrous unsolvated nevirapine (Form-I) in a solvent; Reducing the temperature of the solution to crystallize the dissolved nevirapine as a metastable unsolvated crystalline form (Form IV) of nevirapine; Separating the metastable unsolvated crystalline form (Form-IV) from nevirapine from the solvent; and passing the metastable unsolvated crystalline form (Form IV) from nevirapine to particulate anhydrous unsolvated nevirapine (Form I). The method of claim 9, wherein the solvent is in the form of methanol. The method of claim 10, wherein the step of preparing the solution of the anhydrous unsolvated nevirapine (Form-I) in methanol comprises the further step of raising the temperature of the methanol to within 10 degrees Celsius below the boiling point of methanol. The method of claim 11, wherein the step of reducing the temperature of the solution comprises the step of reducing the temperature at a rate of at least 50 degrees Celsius per hour. The method of claim 12, wherein the step of reducing the temperature of the solution comprises the further step of stirring the solution while the temperature is reduced, resulting in a metastable unsolvated crystalline form (Form-IV). The method of any one of claims 10 to 13, wherein the step of separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the methanol solvent comprises the step of removing the methanol by stripping the methanol from the nevirapine and allowing any residual methanol to evaporate , The method of claim 14, wherein the step of passing the metastable unsolvated crystalline (Form-IV) to particulate anhydrous unsolvated nevirapine (Form-I) comprises the further step of spontaneously disintegrating the metastable unsolvated crystalline Form-IV upon removal of the methanol To form powder having a maximum average particle size of less than 125 microns. A particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable according to the method of any of claims 9 to 15. A medicament obtainable from the particulate anhydrous unsolvated form of nevirapine (Form-I) according to the process of any one of claims 9 to 15, together with at least one inert pharmaceutically acceptable carrier or diluent, in the dosage form selected from the group of tablets; capsules; powders; Solutions; syrups; suspensions; bolus injections; continuous infusions; Powders for dissolution; Anoint; creams; gels; lotions; Sprays, enemas, effervescents, pessaries, transdermal patches, dermal plasters and lozenges. A method of treating a patient suffering from a condition of immunodeficiency, comprising the step of administering to such a patient a pharmaceutically effective amount of the particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable according to the method of any one of claims 9 to 15 , Use of a pharmaceutically effective amount of the particulate anhydrous unsolvated form of nevirapine (Form-I) obtainable according to the method of any one of claims 9 to 15 in a method of. Treatment of a patient suffering from a state of immunodeficiency. A composition comprising a metastable unsolvated crystalline form (Form-IV) of nevirapine, substantially as herein described and exemplified with reference to the accompanying figures. A process for preparing a particulate anhydrous unsolvated form of nevirapine (Form-I), substantially as described herein and exemplified with reference to the accompanying figures.

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