WO2011073907A1 - A polymorph form of nevirapine and its preparation - Google Patents
A polymorph form of nevirapine and its preparation Download PDFInfo
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- WO2011073907A1 WO2011073907A1 PCT/IB2010/055808 IB2010055808W WO2011073907A1 WO 2011073907 A1 WO2011073907 A1 WO 2011073907A1 IB 2010055808 W IB2010055808 W IB 2010055808W WO 2011073907 A1 WO2011073907 A1 WO 2011073907A1
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- nevirapine
- unsolvated
- metastable
- methanol
- crystalline form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- This invention relates to a novel polymorph form of a composition. More particularly, this invention relates to a novel polymorph 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. This invention further relates to a method of producing a particulate anhydrous unsolvated form of nevirapine.
- Nevirapine is a well-known anti-retroviral drug used in the treatment of HIV-1 (human immunodeficiency virus, type 1) infection and AIDS. It is a non-nucleoside reverse transcriptase inhibitor and specifically inhibits HIV- 1 reverse transcriptase. Structurally, nevirapine is a member of the dipyridodiazepinone chemical class of compounds.
- Nevirapine is currently available in two dosage forms, namely tablets (anhydrous form) and in suspensions (hemi-hydrate form).
- the mean particle sizes of commercially available nevirapine are generally larger than 50 pm and typically 125 pm.
- Anhydrous nevirapine refers to the known unsolvated/unhydrated form of nevirapine, currently available commercially and described in US patent 5366972. For the purpose of this application, this form will be referred to as the original "Form-I" polymorph of nevirapine. Nevirapine crystalline Form-ll and Form-Ill are described in both USA patent applications US 20050059653A1 and US20060183738A1.
- a first disadvantage experienced in the preparation of commercially available unsolvated/unhyd rated nevirapine is that the mean particle size of the raw material is relatively too large.
- the raw material therefore has to be ground or milled to obtain the preferred particle size that will allow for handling and processing. Usually this means reducing the mean particle size to 125 ⁇ or less.
- a disadvantage associated with the grinding or milling process is that the process generates heat, which may negatively 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 may negatively affect the stability of the nevirapine end product.
- a further disadvantage of the grinding or milling process is that the equipment, set up, running and operational costs are relatively high.
- 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 method of producing a particulate anhydrous unsolvated form of nevirapine (Form-I).
- Yet another object of the invention is to provide a medicament prepared in accordance with such a method with which the aforesaid disadvantages may be overcome or at least minimised.
- composition comprising a metastable unsolvated crystalline form (Form- IV) of nevirapine.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine may exhibit an x-ray powder diffraction pattern comprising at least one characteristic peak at approximately 7.1° to 7.5° two theta.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine may display a differential scanning calorimetry exothermic transition having an onset temperature in the range of between 70 degrees Celsius and 100 degrees Celsius.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine may display a derivative thermogravimetry trace as depicted in figure 2, having weight loss less than 2% prior to 200 degrees Celsius.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine displays x-ray diffraction pattern, as based on 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 two theta.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine may display an experimental x-ray diffraction pattern: 7.52, 11.71 , 12.65, 13.49, 14.29, 14.61 , 15.49, 17.22, 17.68, 18.80, 19.48, 20.13, 20.78, 21.64, 21.75, 23.07, 23.34, 23.85, 24.64, 25.46, 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 two theta.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine may be in particulate form and the particles may have a mean maximum diameter of less than 125 pm.
- a method of producing a particulate anhydrous unsolvated form of nevirapine including the steps of:
- the solvent is in the form of methanol.
- the maximum mean diameter of the transformed particulate anhydrous unsolvated nevirapine which forms may be less than 125 pm.
- the particle size distribution of the formed particulate anhydrous unsolvated nevirapine (Form-I) is within a relatively narrower range than anhydrous unsolvated nevirapine (Form-I) subjected to grinding/milling in accordance with prior art methods.
- the step of preparing a solution of anhydrous unsolvated nevirapine (Form-I) in methanol may include the further step of elevating 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.
- the step of reducing the temperature of the solution may include the step of stirring the solution whilst the temperature is reduced, rendering a metastable unsolvated crystalline form (Form-IV).
- the step of separating the metastable unsolvated crystalline form (Form- IV) of nevirapine from the methanol solvent may include the step of removing the methanol by draining the methanol from the nevirapine and allowing any residual methanol to evaporate.
- the step of allowing the metastable unsolvated crystalline (Form-IV) to transform to particulate anhydrous unsolvated nevirapine (Form-I) may include the step of allowing the metastable unsolvated crystalline Form-IV to spontaneously disintegrate on removal of the methanol, to form a powder with a maximum mean particle size of less than 125 ym.
- a particulate anhydrous unsolvated form of nevirapine prepared according to the second aspect of the invention.
- a medicament prepared from particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention.
- a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention in a method of preparing a medicament for use in treating a patient suffering from opportunistic disease associated with immune deficiency conditions.
- a method of treating a patient suffering from an immune deficiency condition including the step of administering to such a patient a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention.
- a medicament prepared from particulate anhydrous unsolvated form of nevirapine in accordance with the method of the second aspect of the invention, together with at least one inert pharmaceutically acceptable carrier or diluents in the dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for reconstitution; ointments; creams; gels; lotions; sprays; enemas; douche; pessary; transdermal patch; dermal patch and lozenges.
- figure 1 is a DSC (differential scanning calorimetry) trace of metastabie unsolvated crystalline form (Form-IV) of nevirapine according to one embodiment of the invention.
- DSC differential scanning calorimetry
- Form-IV metastabie unsolvated crystalline form
- DSC Shimadzu DSC-60A (Japan) with TA60 version 2.11 software. Samples were weighed and heated in closed aluminium crucibles. Samples were heated at 10 K/min in an inert nitrogen atmosphere. The DSC was calibrated with a known quantity of Indium.
- figure 2 is a DTG (derivative thermogravimetry) trace of said metastabie unsolvated crystalline form (Form-IV) of nevirapine.
- TGA Shimadzu DTG-60 (Japan) with TA60 version 2.11 software. Samples were heated from 25 degrees Celsius to 300 degrees Celsius at 10 K/min, in open aluminium crucibles. Nitrogen gas was used as inert atmosphere.
- figure 3 is a characteristic XRPD (x-ray powder diffraction pattern) of said metastable unsolvated crystalline form (Form-IV) of nevirapine (top) and transformation to particulate anhydrous unsolvated form of nevirapine (Form-I) according to another aspect of the invention over time at ambient temperature.
- figure 4 is a simulated XRPD pattern of said metastable unsolvated crystalline form (Form-IV) of nevirapine computed using the single crystal x-ray structure of the isostructural ethanol solvate with the solvent contribution suppressed (Vertical axis: Relative intensity; Horizontal axis: 2 Theta (degrees)); figure 5: is an experimental XRPD pattern of a sample of metastable unsolvated crystalline form (Form-IV) of nevirapine (Vertical axis: Intensity (CPS); Horizontal axis: 2 Theta (degrees)); are SEM (scanning electron microscope) images comparing the particulate anhydrous unsolvated form of nevirapine (Form-I) prepared using the method according to a preferred embodiment of the invention (figures 10 and 11), to commercial raw materials obtained from suppliers (figures 10 and 11), to commercial raw materials obtained from suppliers (figures 10 and 11), to commercial raw materials obtained from suppliers
- Figures 6, 8 and 10 feature 1000x magnification and figures 7, 9 and 11 feature 4000x magnification.
- figure 12 depicts a proposed ball-and-stick representation and space-filling mode crystal structure representing metastabie unsolvated crystalline form (Form-IV) of nevirapine computed using the single crystal x-ray structure of the isostructural ethanol solvate with the solvent contribution suppressed.
- a method for producing a particulate anhydrous unsolvated form of nevirapine includes the steps of preparing a solution of conventional (prior art) anhydrous unsolvated nevirapine (Form-I) in a solvent in the form of methanol; elevating the temperature of the solution to 10 degrees Celsius below the boiling point of methanol; reducing the temperature of the solution to crystallise the nevirapine in solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine; separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the methanol; and allowing the metastable unsolvated crystalline form (Form- IV) of nevirapine to transform to particulate anhydrous unsolvated nevirapine (Form-I).
- the first step of the method is to prepare a solution of conventional anhydrous unsolvated nevirapine (Form-I) in methanol.
- a saturated solution of nevirapine was prepared in methanol.
- the nevirapine is added to methanol and the temperature is elevated to within 10 degrees Celsius below the boiling point of the methanol (approximately 50 ml methanol per 1 g nevirapine) whilst continuously stirring.
- the subsequent step of reducing the temperature of the solution includes the step of rapidly reducing the temperature of the solution, at a rate of at least 50 degrees Celsius per hour, by either refrigeration or by placing the container in ice-water, resulting in the crystallisation of the nevirapine in solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine.
- the temperature of the solution may be reduced whilst continuously stirring the solution, resulting in the crystallisation of the nevirapine in solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine.
- the crystalline Form-IV of nevirapine is separated from the methanol solvent by removing the methanol.
- the methanol is removed by draining it from the nevirapine and allowing any residual methanol to evaporate.
- the crystalline Form-IV is allowed to spontaneously disintegrate after removal (evaporation) of the methanol and to transform to particulate anhydrous unsolvated nevirapine (Form-I) powder.
- the maximum mean particle size of the particulate anhydrous unsolvated nevirapine (Form-I) powder that forms is less than 125 ⁇ (without any milling step) and that the particle size distribution thereof is within a relatively narrower range than that of conventional anhydrous unsolvated nevirapine subjected to grinding/milling in accordance with prior art methods.
- FIG. 12 illustrates the crystal structure of metastable unsolvated crystalline form (Form-IV) of nevirapine.
- the cross-sectional area of the empty channel has maximum and minimum linear dimensions of ⁇ 3.5 and ⁇ 5.1 A, resulting in an abnormally low crystal density which renders the structure unstable.
- the novel unsolvated crystalline form of nevirapine (Form-IV) is characterised by its x-ray diffractogram.
- the metastable unsolvated crystalline form (Form-IV) of nevirapine exhibits at least one characteristic peak at approximately 7.1 ° to 7.5° 2-theta in unsolvated form.
- the 2-theta values and the intensity percentages of the relevant peaks in the simulated and experimental x-ray powder diffraction pattern of metastable unsolvated crystalline form (Form-IV) of nevirapine are shown in Tables 1 and 2 respectively.
- Table 1 Simulated XRPD data derived from the pattern based on the structure of metastable unsolvated crystalline form (Form-IV) of nevirapine
- the simulated XRPD pattern (figure 4) yields peaks which are essentially in one-to-one correspondence with those in the experimental XRPD pattern of Form-IV (figures 3 (top) and 5). This correspondence supports the predicted structure of Form-IV.
- Form-IV transforms to a particulate anhydrous unsolvated form of nevirapine (Form-I).
- Scanning electron microscope (SEM) images (figures 6 to 11) compared the particulate anhydrous unsolvated form of nevirapine (Form-I) prepared using the preferred method of the invention (figures 10 and 11), to commercial raw materials obtained from suppliers (figures 6 to 9).
- Particle sizing was used to demonstrate the particle characteristics of the particulate anhydrous unsolvated form of nevirapine (Form-I) obtained and found to conform to the British Pharmacopoeia's guidelines for "very fine powders" ( ⁇ 125 ⁇ ).
- Particulate unsolvated anhydrous form of nevirapine is formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions comprising particulate unsolvated anhydrous form of nevirapine (Form-I) adapted for use in human or veterinary medicine.
- the pharmaceutical compositions are presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient and may also contain, if required, other active ingredients.
- the particulate unsolvated anhydrous form of nevirapine (Form-I) are typically formulated for oral, buccal, topical or parenteral administration. Oral administration is the preferred dosage form, particularly in the form of tablets and capsules.
- the pharmaceutical composition for oral administration conveniently takes the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
- Buccal administration compositions take the form of tablets or lozenges formulated in conventional manner.
- the particulate unsolvated anhydrous form of nevirapine is further formulated for parenteral administration by bolus injection or continuous infusion.
- Formulations for injection are presented in unit dosage forms in ampoules, or in multi-dose containers, with an added preservative.
- the compositions further take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient is in powder form for reconstitution with a suitable vehicle.
- the particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in topical applications, comprising ointments, creams, gels, lotions, powders, transdermal patches, dermal patches or sprays prepared in a conventional manner.
- the particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in rectal and vaginal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.
- a convenient daily dosage regime of particulate unsolvated anhydrous form of nevirapine is currently 1 to 2 doses to the total of 100mg to 400mg per day for adults and 2mg to 7mg per kilogram for children, dependent upon the condition of the patient.
- the particulate unsolvated anhydrous form of nevirapine (Form-I) prepared in accordance with the method of the present invention is formulated into a medicament and used in a method of treating a patient suffering from an immune deficiency condition by administering to such a patient a pharmaceutically effective amount thereof of 1 to 2 doses to the total of 100mg to 400mg per day for adults and 2mg to 7mg per kilogram for children, dependent upon the condition of the patient.
Abstract
The invention relates to a metastable unsolvated crystalline form (Form- IV) of nevirapine, having at least one characteristic x-ray powder diffraction peak at approximately 7.1 ° to 7.5° two theta. The invention further relates to a preparation method of producing a particulate anhydrous unsolvated form of nevirapine.
Description
A POLYMORPH FORM OF NEVIRAPINE AND ITS PREPARATION
INTRODUCTION AND BACKGROUND TO THE INVENTION
This invention relates to a novel polymorph form of a composition. More particularly, this invention relates to a novel polymorph 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. This invention further relates to a method of producing a particulate anhydrous unsolvated form of nevirapine.
Nevirapine is a well-known anti-retroviral drug used in the treatment of HIV-1 (human immunodeficiency virus, type 1) infection and AIDS. It is a non-nucleoside reverse transcriptase inhibitor and specifically inhibits HIV- 1 reverse transcriptase. Structurally, nevirapine is a member of the dipyridodiazepinone chemical class of compounds.
Nevirapine is currently available in two dosage forms, namely tablets (anhydrous form) and in suspensions (hemi-hydrate form). The mean particle sizes of commercially available nevirapine are generally larger than 50 pm and typically 125 pm.
Anhydrous nevirapine refers to the known unsolvated/unhydrated form of nevirapine, currently available commercially and described in US patent
5366972. For the purpose of this application, this form will be referred to as the original "Form-I" polymorph of nevirapine. Nevirapine crystalline Form-ll and Form-Ill are described in both USA patent applications US 20050059653A1 and US20060183738A1.
A first disadvantage experienced in the preparation of commercially available unsolvated/unhyd rated nevirapine (Form-I) is that the mean particle size of the raw material is relatively too large. The raw material therefore has to be ground or milled to obtain the preferred particle size that will allow for handling and processing. Usually this means reducing the mean particle size to 125 μηη or less.
A disadvantage associated with the grinding or milling process is that the process generates heat, which may negatively 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 may negatively affect the stability of the nevirapine end product.
A further disadvantage of the grinding or milling process is that the equipment, set up, running and operational costs are relatively high.
Yet a further disadvantage of the grinding or milling process is that some of the very fine particulate nevirapine is lost during the process, thereby
both decreasing yield and creating excess dust within the production facility.
Yet another disadvantage of the grinding or milling process is that the particle size distribution of the milled or ground nevirapine varies over a relatively wide range, negatively impacting the bulk properties, flowability and characteristics of the compound for handling and formulation into 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 method of producing a particulate anhydrous unsolvated form of nevirapine (Form-I). Yet another object of the invention is to provide a medicament prepared in accordance with such a method with which the aforesaid disadvantages may be overcome or at least minimised.
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
exhibit an x-ray powder diffraction pattern comprising at least one characteristic peak at approximately 7.1° to 7.5° two theta.
The metastable unsolvated crystalline form (Form-IV) of nevirapine may display a differential scanning calorimetry exothermic transition having an onset temperature in the range of between 70 degrees Celsius and 100 degrees Celsius.
The metastable unsolvated crystalline form (Form-IV) of nevirapine may display a derivative thermogravimetry trace as depicted in figure 2, having weight loss less than 2% prior to 200 degrees Celsius.
Further according to the invention the metastable unsolvated crystalline form (Form-IV) of nevirapine displays x-ray diffraction pattern, as based on 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 two theta. Yet further according to the invention the metastable unsolvated crystalline form (Form-IV) of nevirapine may display an experimental x-ray diffraction pattern: 7.52, 11.71 , 12.65, 13.49, 14.29, 14.61 , 15.49, 17.22, 17.68, 18.80, 19.48, 20.13, 20.78, 21.64, 21.75, 23.07, 23.34, 23.85, 24.64,
25.46, 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 two theta. The metastable unsolvated crystalline form (Form-IV) of nevirapine may be in particulate form and the particles may have a mean maximum diameter of less than 125 pm.
According to a second aspect of the invention there is provided a method of producing a particulate anhydrous unsolvated form of nevirapine (Form- I) including the steps of:
preparing a solution of anhydrous unsolvated nevirapine (Form-I) in a solvent;
reducing the temperature of the solution to crystallise the nevirapine in solution as a metastable unsolvated crystalline form (Form-IV) of nevirapine;
separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the solvent; and
allowing the metastable unsolvated crystalline form (Form-IV) of nevirapine to transform to particulate anhydrous unsolvated nevirapine (Form-I).
Further according to the invention the solvent is in the form of methanol.
The maximum mean diameter of the transformed particulate anhydrous unsolvated nevirapine which forms may be less than 125 pm. Further according to the invention, the particle size distribution of the formed particulate anhydrous unsolvated nevirapine (Form-I) is within a relatively narrower range than anhydrous unsolvated nevirapine (Form-I) subjected to grinding/milling in accordance with prior art methods. The step of preparing a solution of anhydrous unsolvated nevirapine (Form-I) in methanol may include the further step of elevating 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 whilst the temperature is reduced, rendering a metastable unsolvated crystalline form (Form-IV).
The step of separating the metastable unsolvated crystalline form (Form-
IV) of nevirapine from the methanol solvent may include the step of removing the methanol by draining the methanol from the nevirapine and allowing any residual methanol to evaporate. The step of allowing the metastable unsolvated crystalline (Form-IV) to transform to particulate anhydrous unsolvated nevirapine (Form-I) may include the step of allowing the metastable unsolvated crystalline Form-IV to spontaneously disintegrate on removal of the methanol, to form a powder with a maximum mean particle size of less than 125 ym.
According to a third aspect of the invention there is provided a particulate anhydrous unsolvated form of nevirapine (Form-I) prepared according to the second aspect of the invention. According to a fourth aspect of the invention there is provided a medicament prepared from particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention. According to a fifth aspect of the invention there is provided use of a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention in a method of treating a patient suffering
from an immune compromised condition.
According to a sixth aspect of the invention there is provided use of a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention in a method of preparing a medicament for use in treating a patient suffering from opportunistic disease associated with immune deficiency conditions. According to a seventh aspect of the invention there is provided a method of treating a patient suffering from an immune deficiency condition including the step of administering to such a patient a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of the second aspect of the invention.
According to yet another aspect of the invention there is provided a medicament prepared from particulate anhydrous unsolvated form of nevirapine (Form-I) in accordance with the method of the second aspect of the invention, together with at least one inert pharmaceutically acceptable carrier or diluents in the dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for reconstitution; ointments;
creams; gels; lotions; sprays; enemas; douche; pessary; transdermal patch; dermal patch and lozenges.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described further, by way of example only, with reference to the accompanying drawings wherein: figure 1 : is a DSC (differential scanning calorimetry) trace of metastabie unsolvated crystalline form (Form-IV) of nevirapine according to one embodiment of the invention. DSC: Shimadzu DSC-60A (Japan) with TA60 version 2.11 software. Samples were weighed and heated in closed aluminium crucibles. Samples were heated at 10 K/min in an inert nitrogen atmosphere. The DSC was calibrated with a known quantity of Indium. (Vertical axis: Heat flow (mW); Horizontal axis: temperature (degrees Celsius)); figure 2: is a DTG (derivative thermogravimetry) trace of said metastabie unsolvated crystalline form (Form-IV) of nevirapine. TGA: Shimadzu DTG-60 (Japan) with TA60 version 2.11 software. Samples were heated from 25 degrees Celsius to 300 degrees Celsius at 10
K/min, in open aluminium crucibles. Nitrogen gas was used as inert atmosphere. (Vertical axis (left): Weight (mg); Horizontal axis: temperature (degrees Celsius); Vertical axis (right): microvolt (pV)); figure 3: is a characteristic XRPD (x-ray powder diffraction pattern) of said metastable unsolvated crystalline form (Form-IV) of nevirapine (top) and transformation to particulate anhydrous unsolvated form of nevirapine (Form-I) according to another aspect of the invention over time at ambient temperature. Calculation based on CuKoc-radiation, λ = 1.5418 A. (Vertical axis: Relative intensity; Horizontal axis: 2 Theta (degrees)); figure 4: is a simulated XRPD pattern of said metastable unsolvated crystalline form (Form-IV) of nevirapine computed using the single crystal x-ray structure of the isostructural ethanol solvate with the solvent contribution suppressed (Vertical axis: Relative intensity; Horizontal axis: 2 Theta (degrees)); figure 5: is an experimental XRPD pattern of a sample of metastable unsolvated crystalline form (Form-IV) of
nevirapine (Vertical axis: Intensity (CPS); Horizontal axis: 2 Theta (degrees)); are SEM (scanning electron microscope) images comparing the particulate anhydrous unsolvated form of nevirapine (Form-I) prepared using the method according to a preferred embodiment of the invention (figures 10 and 11), to commercial raw materials obtained from suppliers (figures 6 - 9). (Figures 6, 8 and 10 feature 1000x magnification and figures 7, 9 and 11 feature 4000x magnification.); and figure 12 depicts a proposed ball-and-stick representation and space-filling mode crystal structure representing metastabie unsolvated crystalline form (Form-IV) of nevirapine computed using the single crystal x-ray structure of the isostructural ethanol solvate with the solvent contribution suppressed.
DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
According to a preferred embodiment of the invention there is provided a method for producing a particulate anhydrous unsolvated form of nevirapine (Form-I).
The method includes the steps of preparing a solution of conventional (prior art) anhydrous unsolvated nevirapine (Form-I) in a solvent in the form of methanol; elevating the temperature of the solution to 10 degrees Celsius below the boiling point of methanol; reducing the temperature of the solution to crystallise the nevirapine in solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine; separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the methanol; and allowing the metastable unsolvated crystalline form (Form- IV) of nevirapine to transform to particulate anhydrous unsolvated nevirapine (Form-I).
Further details of respective steps in the method according to the invention:
Preparation of a solution of anhydrous unsolvated nevirapine (Form- I) in a solvent
The first step of the method, according to a preferred embodiment of the invention, is to prepare a solution of conventional anhydrous unsolvated nevirapine (Form-I) in methanol. In the preparation of the solution, a saturated solution of nevirapine was prepared in methanol. The nevirapine is added to methanol and the temperature is elevated to within 10 degrees Celsius below the boiling point of the methanol (approximately 50
ml methanol per 1 g nevirapine) whilst continuously stirring.
The subsequent step of reducing the temperature of the solution, includes the step of rapidly reducing the temperature of the solution, at a rate of at least 50 degrees Celsius per hour, by either refrigeration or by placing the container in ice-water, resulting in the crystallisation of the nevirapine in solution as a new metastable unsolvated crystalline form (Form-IV) of nevirapine. Alternatively the temperature of the solution may be reduced whilst continuously stirring the solution, resulting in the crystallisation of the nevirapine in 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 from the methanol solvent by removing the methanol. The methanol is removed by draining it from the nevirapine and allowing any residual methanol to evaporate.
Transformation of crystalline Form-IV to particulate unsolvated anhydrous nevirapine (Form-I)
According to a further step of the invention, the crystalline Form-IV is allowed to spontaneously disintegrate after removal (evaporation) of the methanol and to transform to particulate anhydrous unsolvated nevirapine (Form-I) powder.
Further analysis and findings
It has surprisingly been found that the maximum mean particle size of the particulate anhydrous unsolvated nevirapine (Form-I) powder that forms is less than 125 μιη (without any milling step) and that the particle size distribution thereof is within a relatively narrower range than that of conventional anhydrous unsolvated nevirapine subjected to grinding/milling in accordance with prior art methods.
A DSC (differential scanning calorimetry) (figurel), DTG (derivative thermogravimetry) (figure 2) trace as well as x-ray powder diffraction patterns (figures 3 to 5) of the new metastable unsolvated crystalline form (Form-IV) of nevirapine was obtained.
From figure 1 , it is evident that Form-IV is not a solvate, because the exotherm shows the transformation to particulate anhydrous unsolvated form of nevirapine (Form-I). The absence of a desolvation endotherm therefore confirms that the structure is not a solvate.
Figure 2 resembles an overlay of the DTA (differential thermal analysis) trace (top trace) and TG (thermogravimetry) trace (bottom trace) of metastable unsolvated crystalline form (Form-IV) of nevirapine. From figure 2 it is therefore evident that Form-IV is not a solvate because there is minimal weight loss prior to the sample reaching 200°C.
Form-IV of nevirapine was found to be isostructural (having the same crystalline structure) to the primary alcohol solvates of nevirapine, but no solvent was included in this structure. It was noted that the PXRD pattern of metastable unsolvated crystalline form (Form-IV) of nevirapine closely resembled the typical PXRD pattern obtained for members of a series of isostructural solvates of nevirapine containing the primary alcohols CH3(CH2)nOH with n = 1 - 7. These solvates crystallise in the triclinic crystal system.
The simulated PXRD pattern of the complete nevirapine framework occurring in ethanol solvate was calculated, and given that the metastable unsolvated crystalline form (Form-IV) of nevirapine is solvent-free, the contribution from the included ethanol molecules was suppressed. Figure 12 illustrates the crystal structure of metastable unsolvated crystalline form (Form-IV) of nevirapine. The cross-sectional area of the empty channel has maximum and minimum linear dimensions of ~3.5 and ~5.1 A, resulting in an abnormally low crystal density which renders the structure
unstable.
The novel unsolvated crystalline form of nevirapine (Form-IV) is characterised by its x-ray diffractogram. The metastable unsolvated crystalline form (Form-IV) of nevirapine exhibits at least one characteristic peak at approximately 7.1 ° to 7.5° 2-theta in unsolvated form. The 2-theta values and the intensity percentages of the relevant peaks in the simulated and experimental x-ray powder diffraction pattern of metastable unsolvated crystalline form (Form-IV) of nevirapine are shown in Tables 1 and 2 respectively.
Table 1 : Simulated XRPD data derived from the pattern based on the structure of metastable unsolvated crystalline form (Form-IV) of nevirapine
2-theta (θ°) d-spacing/ A Relative Indices h k 1 of the principal contributors intensity 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 04
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/ A 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 3.81 155 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 (figure 4) yields peaks which are essentially in one-to-one correspondence with those in the experimental XRPD pattern of Form-IV (figures 3 (top) and 5). This correspondence supports the predicted structure of Form-IV.
A perfect match between the XRPD patterns of figure 4 and figures 3 (top) and 5 was not expected, for the reason that in a single crystal all the unit cells have the same orientation relative to incoming x-ray radiation. In a powder, each crystallite has its own orientation relative to the incoming beam of x-ray radiation. Instead of displaying single points of deflected x- ray concentrations such as for a single crystal, halos of respective concentrations are displayed on XRPD patterns, making analysis of the diffraction pattern relatively more complex.
If left to dry (at regular atmospheric conditions), Form-IV transforms to a particulate anhydrous unsolvated form of nevirapine (Form-I). Scanning electron microscope (SEM) images (figures 6 to 11) compared the particulate anhydrous unsolvated form of nevirapine (Form-I) prepared
using the preferred method of the invention (figures 10 and 11), to commercial raw materials obtained from suppliers (figures 6 to 9). Particle sizing was used to demonstrate the particle characteristics of the particulate anhydrous unsolvated form of nevirapine (Form-I) obtained and found to conform to the British Pharmacopoeia's guidelines for "very fine powders" (< 125 μιτι).
It will be appreciated that the disadvantages of prior art methods of preparing conventional anhydrous unsolvated nevirapine (Form-I) are alleviated with a method according to the invention for preparing particulate anhydrous unsolvated form of nevirapine (Form-I). In particular, no milling or grinding and subsequent sieving of the formed particulate anhydrous unsolvated form of nevirapine (Form-I) is required after formation thereof. It was found that the flowability of the formed particulate anhydrous unsolvated form of nevirapine (Form-I) is far superior to conventional anhydrous unsolvated nevirapine (Form-I). This is attributed to the shape of the particles that form and the narrow band of particle size distribution. It was found that a method according to the invention for forming particulate unsolvated anhydrous form of nevirapine (Form-I) presents a relatively cheaper alternative to conventional methods, and also presents a product that is superior in many respects to conventional anhydrous
unsolvated nevirapine (Form-I).
Particulate unsolvated anhydrous form of nevirapine (Form-I) is formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions comprising particulate unsolvated anhydrous form of nevirapine (Form-I) adapted for use in human or veterinary medicine.
The pharmaceutical compositions are presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient and may also contain, if required, other active ingredients. The particulate unsolvated anhydrous form of nevirapine (Form-I) are typically formulated for oral, buccal, topical or parenteral administration. Oral administration is the preferred dosage form, particularly in the form of tablets and capsules. The pharmaceutical composition for oral administration conveniently takes the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. Buccal administration compositions take the form of tablets or lozenges formulated in conventional manner.
The particulate unsolvated anhydrous form of nevirapine (Form-I) is further formulated for parenteral administration by bolus injection or continuous
infusion. Formulations for injection are presented in unit dosage forms in ampoules, or in multi-dose containers, with an added preservative. The compositions further take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient is in powder form for reconstitution with a suitable vehicle.
The particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in topical applications, comprising ointments, creams, gels, lotions, powders, transdermal patches, dermal patches or sprays prepared in a conventional manner.
The particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in rectal and vaginal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.
For oral administration a convenient daily dosage regime of particulate unsolvated anhydrous form of nevirapine (Form-I) is currently 1 to 2 doses to the total of 100mg to 400mg per day for adults and 2mg to 7mg per kilogram for children, dependent upon the condition of the patient.
The particulate unsolvated anhydrous form of nevirapine (Form-I) prepared in accordance with the method of the present invention is formulated into a medicament and used in a method of treating a patient suffering from an immune deficiency condition by administering to such a patient a pharmaceutically effective amount thereof of 1 to 2 doses to the total of 100mg to 400mg per day for adults and 2mg to 7mg per kilogram for children, dependent upon the condition of the patient.
It will be appreciated further that variations in detail are possible with a method for preparing a medicament and a medicament prepared with such a method, according to the invention without departing from the scope of the appended claims.
Claims
A composition comprising a metastable unsoivated crystalline form (Form-IV) of nevirapine.
A composition according to claim 1 , wherein said metastable unsoivated crystalline form (Form-IV) of nevirapine exhibits an x-ray powder diffraction pattern comprising at least one characteristic peak at approximately 7.1° to 7.5° two theta.
A composition according to claim 1 or claim 2 wherein the metastable unsoivated crystalline form (Form-IV) of nevirapine displays a differential scanning calorimetry exotherm transition having an onset temperature in the range of between 70 degrees Celsius and 100 degrees Celsius.
A composition according to any one of claims 1 to 3 wherein the metastable unsoivated crystalline form (Form-IV) of nevirapine displays a derivative thermogravimetry trace as depicted in figure 2, having less that 2% weight loss up to 200 degrees Celsius.
A composition according to anyone of claims 1 to 4 wherein the metastable unsoivated crystalline form (Form-IV) of nevirapine has a
caculated 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 two theta.
A composition according to claim 1 wherein the metastable unsolvated crystalline form (Form-IV) of nevirapine has an experimental x-ray diffraction pattern of 7.52, 11.71 , 12.65, 13.49, 14.29, 14.61 , 15.49, 17.22, 17.68, 18.80, 19.48, 20.13, 20.78, 21.64, 21.75, 23.07, 23.34, 23.85, 24.64, 25.46, 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 two 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 a mean maximum diameter of less than 125 μηη.
A composition according to any one of claims 1 to 7 having a crystal structure, substantially as illustrated in figure 12.
A method of producing a particulate anhydrous unsolvated form of nevirapine (Form-I) including the steps of preparing a solution of anhydrous unsolvated nevirapine (Form-I) in a solvent; reducing the
temperature of the solution to crystallise the nevirapine in solution as a metastable unsolvated crystalline form (Form-IV) of nevirapine; separating the metastable unsolvated crystalline form (Form-IV) of nevirapine from the solvent; and allowing the metastable unsolvated crystalline form (Form-IV) of nevirapine to transform to particulate anhydrous unsolvated nevirapine (Form-I).
10. A method according to claim 9 wherein the solvent is in the form of methanol.
11. A method according to claim 10 wherein the step of preparing the solution of the anhydrous unsolvated nevirapine (Form-I) in methanol includes the further step of elevating the temperature of the methanol to within 10 degrees Celsius below the boiling point of methanol.
12. A method according to claim 11 wherein the step of reducing the temperature of the solution includes the step of reducing the temperature at a rate of at least 50 degrees Celsius per hour. 3. A method according to claim 12 wherein the step of reducing the temperature of the solution includes the further step of stirring the solution whilst the temperature is reduced, rendering a metastable unsolvated crystalline form (From-IV).
14. A method according to 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 includes the step of removing the methanol by draining the methanol from the nevirapine and allowing any residual methanol to evaporate.
15. A method according to claim 14 wherein the step of allowing the metastable unsolvated crystalline (Form-IV) to transform to particulate anhydrous unsolvated nevirapine (Form-I) includes the further step of allowing the metastable unsolvated crystalline Form-IV to spontaneously disintegrate on removal of the methanol, to form a powder with a maximum mean particle size of less than 125 pm. 16. A particulate anhydrous unsolvated form of nevirapine (Form-I) prepared according to the method of any one of claims 9 to 15.
17. A medicament prepared from particulate anhydrous unsolvated form of nevirapine (Form-I) in accordance with the method of any one of claims 9 to 15 together with at least one inert pharmaceutically acceptable carrier or diluents in the dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for
reconstitution; ointments; creams; gels; lotions; sprays, enemas, douche, pessary, transdermal patches, dermal patches and lozenges.
18. A method of treating a patient suffering from an immune deficiency condition including the step of administering to such a patient a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of any one of claims 9 to 15. 19. Use of a pharmaceutically effective amount of particulate anhydrous unsolvated form of nevirapine (Form-I) prepared in accordance with the method of any one of claims 9 to 15 in a method of treating a patient suffering from an immune compromised condition. 20. A composition comprising a metastable unsolvated crystalline form (Form-IV) of nevirapine substantially as herein described and exemplified with reference to the accompanying figures.
21. A method of producing a particulate anhydrous unsolvated form of nevirapine (Form-I) substantially as herein described and exemplified, with reference to the accompanying figures.
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| CN2010800612262A CN102725293A (en) | 2009-12-17 | 2010-12-14 | A polymorph form of nevirapine and its preparation |
| DE112010004862T DE112010004862T5 (en) | 2009-12-17 | 2010-12-14 | Polymorphic form of nevirapine and its preparation |
| BR112012014762A BR112012014762A2 (en) | 2009-12-17 | 2010-12-14 | polymorphic form of nevirapine and its preparation |
| ZA2012/04410A ZA201204410B (en) | 2009-12-17 | 2012-06-15 | A polymorph form of nevirapine and its preparation |
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| CN (1) | CN102725293A (en) |
| BR (1) | BR112012014762A2 (en) |
| DE (1) | DE112010004862T5 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20130039987A1 (en) * | 2009-11-10 | 2013-02-14 | North-West University | Method for increasing the solubility of a transcriptase inhibitor composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366972A (en) | 1989-04-20 | 1994-11-22 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection |
| WO1999009990A1 (en) * | 1997-08-25 | 1999-03-04 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical suspension comprising nevirapine hemihydrate |
| US20050059653A1 (en) | 2002-06-21 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Novel crystalline forms of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4] diazepin-6-one (nevirapine) |
| WO2007010352A1 (en) * | 2005-07-19 | 2007-01-25 | Emcure Pharmaceuticals Limited | An improved process for industrial manufacture of nevirapine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4403311C1 (en) * | 1994-02-03 | 1995-04-20 | Boehringer Ingelheim Kg | Process for the preparation of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4-d iazepin]-6-one) |
| UA80140C2 (en) * | 2002-06-28 | 2007-08-27 | Boehringer Ingelheim Chemicals | Improved method of making nevirapine, intermediate (variants) |
-
2010
- 2010-12-14 WO PCT/IB2010/055808 patent/WO2011073907A1/en active Application Filing
- 2010-12-14 BR BR112012014762A patent/BR112012014762A2/en not_active Application Discontinuation
- 2010-12-14 DE DE112010004862T patent/DE112010004862T5/en not_active Withdrawn
- 2010-12-14 CN CN2010800612262A patent/CN102725293A/en active Pending
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2012
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366972A (en) | 1989-04-20 | 1994-11-22 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection |
| WO1999009990A1 (en) * | 1997-08-25 | 1999-03-04 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical suspension comprising nevirapine hemihydrate |
| US20050059653A1 (en) | 2002-06-21 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Novel crystalline forms of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4] diazepin-6-one (nevirapine) |
| US20060183738A1 (en) | 2002-06-21 | 2006-08-17 | Reguri Buchi R | Crystalline forms of nevirapine |
| WO2007010352A1 (en) * | 2005-07-19 | 2007-01-25 | Emcure Pharmaceuticals Limited | An improved process for industrial manufacture of nevirapine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130039987A1 (en) * | 2009-11-10 | 2013-02-14 | North-West University | Method for increasing the solubility of a transcriptase inhibitor composition |
| US9273049B2 (en) * | 2009-11-10 | 2016-03-01 | North-West University | Method for increasing the solubility of nevirapine |
Also Published As
| Publication number | Publication date |
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| ZA201204410B (en) | 2013-02-27 |
| CN102725293A (en) | 2012-10-10 |
| BR112012014762A2 (en) | 2016-03-29 |
| DE112010004862T5 (en) | 2012-12-06 |
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