WO2017190715A1 - An amorphous form of sofosbuvir, a method of its preparation and its stabilization - Google Patents
An amorphous form of sofosbuvir, a method of its preparation and its stabilization Download PDFInfo
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- WO2017190715A1 WO2017190715A1 PCT/CZ2017/000034 CZ2017000034W WO2017190715A1 WO 2017190715 A1 WO2017190715 A1 WO 2017190715A1 CZ 2017000034 W CZ2017000034 W CZ 2017000034W WO 2017190715 A1 WO2017190715 A1 WO 2017190715A1
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- sofosbuvir
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- the invention relates to an amorphous form of sofosbuvir of formula I, (S)-isopropyl 2-((S)- (((2R,3R 1 4R,5R)-5-(2,4-dioxo-3,4-dmydropyrimidm-l(2H)-yl)-4-fluoro-3-hydroxy-4- -(phenoxy)phosphorylamino)propanoate,
- Sofosbuvir is a well-known drug used for the treatment of type C chronical hepatitis.
- the compound was first described in the patent application WO2008121634. Reproduction of the preparation procedure described in this document provided an amorphous substance that was very difficult to purify.
- the application WO2011123645 describes another crystalline form 6. It has so far proved to be the most suitable crystalline form for pharmaceutical processing. In spite of this, more forms are being looked for. It is difficult to combine all the required characteristics as good stability and suitable solubility.
- the application WO2015099989 describes crystalline forms 7 and 8. However, their properties related to the possibility of preparation of a pharmaceutical composition are not described. They do not appear to be better than those of the earlier described form 1.
- Every pharmaceutical Company strives to use the most stable solid form of the active pharmaceutical ingredient in its medicinal product.
- the stability Of the form corresponds to its melting point to a certain extent.
- crystalline substances exhibit much lower solubility and bioavailability as compared to amorphous substances.
- the invention provides a method of increasing the stability of amorphous sofosbuvir consisting in aging of the prepared amorphous form at a temperature of 0 to 90°C in an air environment with a relative humidity of 0 to 50% (RH) for 1 to 90 days.
- This method is preferably applied to the amorphous substance of sofosbuvir prepared by hot melt extrusion at 100 to 140°C.
- Sofosbuvir in the amorphous form has the glass transition temperature Tg of at least 50°C.
- the essence of the present invention is an amorphous form of sofosbuvir prepared using the hot melt extrusion (HME) method, its stabilization and its use in a drug form.
- Stabilization of the amorphous form of sofosbuvir and generally of all amorphous forms is carried out by exposing the substance to the conditions of a dry environment or by addition of silica or another substance that is able to adsorb moisture to protect the molecules of the entire active pharmaceutical ingredient (API), in this case sofosbuvir.
- HME hot melt extrusion
- the amorphous form of sofosbuvir prepared by hot melt extrusion exhibits a different character of particles than an amorphous form of sofosbuvir prepared using the common preparation method of amorphous substances - spray drying, it is characterized by a smaller surface area of particles and it is not prone to adsorb moisture from the ambient environment to such an extent. In spite of this, it is suitable to stabilize the amorphous form prepared this way even more by adding silica to minimize the influence of atmospheric humidity.
- the glass transition temperature of an amorphous substance is a prominent indication of its stability. It is a well-known fact that the higher the glass transition temperature is, the more stable is the amorphous substance. Therefore, effort is made to obtain an amorphous form with the highest possible glass transition temperature while one of the most important parameters influencing the glass transition temperature is the content of residual solvents, or water, respectively.
- An amorphous form of sofosbuvir prepared using the hot melt extrusion method or spray drying exhibits a glass transition temperature in the range of 46°C to 49°C, determined by means of differential scanning calorimetry. However, if amorphous sofosbuvir is exposed to the influence of a dry environment for a period on the order of days, its glass transition temperature will rise.
- the glass transition temperature of amorphous sofosbuvir prepared by spray drying will rise after 30 days' exposure to 25% relative humidity and the temperature of 40°C from the original 48.9°C (Fig. 1) to 54.6°C (Fig. 2) and after 30 days' exposure to 0% relative humidity and the temperature of 40°C it will rise to 63.2°C (Fig. 3).
- the glass transition temperature of amorphous sofosbuvir prepared by hot melt temperature rose after 30 days' exposure to 25% relative humidity and the temperature of 40°C from the original 45.9°C (Fig. 4) to 54.3°C (Fig. 5) and after 30 days' exposure to 0% relative humidity and the temperature of 40°C it rose to 64.5°C (Fig. 6).
- Amorphous forms of active pharmaceutical ingredients that are prepared using the most common preparation method - spray drying have a high specific surface area and consequently tendency to adsorb water.
- amorphous forms prepared by spraying have a high electrostatic charge and they are difficult to handle.
- An amorphous form prepared by hot melt extrusion has a much higher density and it can be subsequently ground to the required particle size to influence the specific surface area value.
- An amorphous substance prepared this way actually partially exhibits some properties of a crystalline matter and its processing is much easier.
- the amorphous form of sofosbuvir prepared by hot melt extrusion does not have such a high tendency to run in a wet environment as the amorphous form prepared by spray drying.
- This fact can be further supported by an addition of a substance that preferentially adsorbs moisture, protection the entire API.
- a substance that preferentially adsorbs moisture protection the entire API.
- Si dioxide, or silica can be used as such a substance.
- Types of silica are known that are approved for use in the pharmaceutical industry.
- An addition of such silica supported stability of the amorphous form of sofosbuvir even further and higher stability against climatic influences was registered.
- the amorphous samples of sofosbuvir obtained by means of extrusion were prepared with the use of a HAAKETM MiniLab II double-screw micro-kneader with the chamber volume of 7 ml. The material was dosed manually. The rotational speed of the worms was 120 rpm. Theexperiments were carried out at a chamber temperature of 100 to 120°C.
- the amorphous form of sofosbuvir prepared with the use of the method according to this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets.
- Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. microcrystalline cellulose), binders (e.g. povidone), disintegrants (e.g. crospovidone), lubricants (e.g. magnesium stearate), surfactants etc.
- These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
- tablets containing the amorphous form of sofosbuvir were produced.
- the method of wet granulation by ethanol with subsequent fluid drying or the method of direct mixing (direct compression) was used. It was followed by the production of tablets. Examples of the said compositions and the description of the production procedures are included in the experimental part. Subsequent analysis confirmed that no polymorphic change of the active pharmaceutical ingredient (API) had occurred and during the production process the chemical purity of the API had been preserved.
- API active pharmaceutical ingredient
- Fig. 1 DSC record of the amorphous form of sofosbuvir prepared by spray drying
- Fig. 2 DSC record of the amorphous form of sofosbuvir prepared by spray drying
- Fig. 3 DSC record of the amorphous form of sofosbuvir prepared by spray drying
- Fig. 4 DSC record of the amorphous form of sofosbuvir prepared by spray drying
- Fig. 5 DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion
- Fig. 6 DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 25% RH and 40°C for 30 days
- Fig. 7 DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 0% RH and 40°C for 30 days
- Fig. 8 DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 75% RH and 40°C for 30 days
- laboratory temperature refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C.
- Sofosbuvir was extruded using a HAAKETM MiniLab II double-screw micro-kneader in the range of 10 to 150 g.
- the material was dosed manually.
- the rotary speed of the worms was 120 rpm. Chamber temperature 100°C. This way, amorphous samples without a crystalline admixture were repeatedly obtained.
- the product yields varied in the range of 90 to 95%.
- Sofosbuvir (amorphous form) was granulated by ethanol together with microcrystalline cellulose, crospovidone and povidone. The granulate was dried in a fluid drier and sieved. Prosolv (microcrystalline cellulose with a silica layer), the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 1210 mg/tablet. The cores produced this way showed suitable parameters as abrasion, disintegration and dissolution rate of the active ingredient during analytic tests.
- Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used.
- Sofosbuvir (amorphous form) was granulated by ethanol together with microcrystalline cellulose, crospovidone and povidone. The granulate was dried in a fluid drier and sieved. Prosolv (microcrystalline cellulose with a silica layer), the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 1000 mg/tablet. The cores produced this way showed suitable parameters as abrasion, disintegration and dissolution rate of the active ingredient during analytic tests.
- Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used.
- Sofosbuvir (amorphous form) was granulated by ethanol together with crospovidone and povidone. The granulate was dried in a fluid drier and sieved through a sieve with the mesh size of 0.8 mm. Prosolv (microcrystalline cellulose with a silica layer), microcrystalline cellulose, the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 667 mg tablet. The flow properties of the material met the tabletting parameters. Suitable disintegration, abrasion and dissolution and stability characteristics of the resulting tablets were also achieved.
- Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used.
- the records of differential scanning calorimetry were measured using a Discovery DSC device made by TA Instruments.
- the sample charge in a standard Al pot (40 ⁇ ,) was between 3 and 4 mg and the heating rate was 5°C/min.
- As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.
Abstract
The invention relates to a preparation method of an amorphous form of sofosbuvir of formula I, (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4- fluoro-3-hydroxy-4-memyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)- propanoate, in particular aging of the amorphous form at a temperature of 0 to 90°C in an air environment with relative humidity of 0 to 50% RH for 1 to 90 days and its use in a drug form.
Description
An amorphous form of sofosbuvir, a method of its preparation and its stabilization
Field of the Invention The invention relates to an amorphous form of sofosbuvir of formula I, (S)-isopropyl 2-((S)- (((2R,3R14R,5R)-5-(2,4-dioxo-3,4-dmydropyrimidm-l(2H)-yl)-4-fluoro-3-hydroxy-4- -(phenoxy)phosphorylamino)propanoate,
in particular to a method of its preparation, its stabilization and use in a drug form.
Background Art
Sofosbuvir is a well-known drug used for the treatment of type C chronical hepatitis. The compound was first described in the patent application WO2008121634. Reproduction of the preparation procedure described in this document provided an amorphous substance that was very difficult to purify.
Another patent application WO2010135569 described sofosbuvir in crystalline forms identified as 1 to 5. Out of these five forms, only one turned out to be stable, namely form 1. But even this form was hygroscopic, i.e. not very suitable for pharmaceutical processing. The application also described a preparation procedure of an amorphous substance. However, in this form, sofosbuvir appeared to be strongly hygroscopic and its processing into a pharmaceutical composition required special modifications.
The application WO2011123645 describes another crystalline form 6. It has so far proved to be the most suitable crystalline form for pharmaceutical processing.
In spite of this, more forms are being looked for. It is difficult to combine all the required characteristics as good stability and suitable solubility. For example, the application WO2015099989 describes crystalline forms 7 and 8. However, their properties related to the possibility of preparation of a pharmaceutical composition are not described. They do not appear to be better than those of the earlier described form 1.
The same applies to the forms identified as A to D described in the application WO2015126995. Thus, it appears worth looking for more crystalline forms. The current required properties of the active ingredient for a pharmaceutical composition may change due to changes of requirements for properties of the drug (e.g. slower dissolution).
Disclosure of the Invention
Every pharmaceutical Company strives to use the most stable solid form of the active pharmaceutical ingredient in its medicinal product. In the case of crystalline forms the stability Of the form corresponds to its melting point to a certain extent. On the other hand, crystalline substances exhibit much lower solubility and bioavailability as compared to amorphous substances. With regard to these facts, it is advantageous to prepare an amorphous form of the active pharmaceutical ingredient, which is more readily soluble, exhibiting higher bioavailability.
Accordingly, the invention provides a method of increasing the stability of amorphous sofosbuvir consisting in aging of the prepared amorphous form at a temperature of 0 to 90°C in an air environment with a relative humidity of 0 to 50% (RH) for 1 to 90 days.
This method is preferably applied to the amorphous substance of sofosbuvir prepared by hot melt extrusion at 100 to 140°C.
Sofosbuvir in the amorphous form has the glass transition temperature Tg of at least 50°C.
Detailed description of the Invention
The essence of the present invention is an amorphous form of sofosbuvir prepared using the hot melt extrusion (HME) method, its stabilization and its use in a drug form. Stabilization of the amorphous form of sofosbuvir and generally of all amorphous forms is carried out by exposing the substance to the conditions of a dry environment or by addition of silica or another substance that is able to adsorb moisture to protect the molecules of the entire active pharmaceutical ingredient (API), in this case sofosbuvir.
The amorphous form of sofosbuvir prepared by hot melt extrusion exhibits a different character of particles than an amorphous form of sofosbuvir prepared using the common preparation method of amorphous substances - spray drying, it is characterized by a smaller surface area of particles and it is not prone to adsorb moisture from the ambient environment to such an extent. In spite of this, it is suitable to stabilize the amorphous form prepared this way even more by adding silica to minimize the influence of atmospheric humidity.
The glass transition temperature of an amorphous substance is a prominent indication of its stability. It is a well-known fact that the higher the glass transition temperature is, the more stable is the amorphous substance. Therefore, effort is made to obtain an amorphous form with the highest possible glass transition temperature while one of the most important parameters influencing the glass transition temperature is the content of residual solvents, or water, respectively. An amorphous form of sofosbuvir prepared using the hot melt extrusion method or spray drying exhibits a glass transition temperature in the range of 46°C to 49°C, determined by means of differential scanning calorimetry. However, if amorphous sofosbuvir is exposed to the influence of a dry environment for a period on the order of days, its glass transition temperature will rise. The glass transition temperature of amorphous sofosbuvir prepared by spray drying will rise after 30 days' exposure to 25% relative humidity and the temperature of 40°C from the original 48.9°C (Fig. 1) to 54.6°C (Fig. 2) and after 30 days' exposure to 0% relative humidity and the temperature of 40°C it will rise to 63.2°C (Fig. 3). The glass transition temperature of amorphous sofosbuvir prepared by hot melt temperature rose after 30 days' exposure to 25% relative humidity and the temperature of 40°C from the original 45.9°C (Fig. 4) to 54.3°C (Fig. 5) and after 30 days' exposure to 0% relative humidity and the temperature of 40°C it rose to 64.5°C (Fig. 6). In an environment with lower relative humidity, amorphous sofosbuvir becomes more stable and remains in the form of a loose substance. However, in an environment with 75% relative humidity, the amorphous form of
sofosbuvir starts to run and crystallizes to form X, which exhibits a melting temperature of approx. 116.5°C. The results of these tests are summarized in Table 1.
Table 1: Environmental impact on behavior of the amorphous form of sofosbuvir
Amorphous forms of active pharmaceutical ingredients that are prepared using the most common preparation method - spray drying have a high specific surface area and consequently tendency to adsorb water. At the same time, amorphous forms prepared by spraying have a high electrostatic charge and they are difficult to handle. An amorphous form prepared by hot melt extrusion has a much higher density and it can be subsequently ground to the required particle size to influence the specific surface area value. An amorphous substance prepared this way actually partially exhibits some properties of a crystalline matter and its processing is much easier.
With regard to its specific surface area, the amorphous form of sofosbuvir prepared by hot melt extrusion does not have such a high tendency to run in a wet environment as the amorphous form prepared by spray drying. This fact can be further supported by an addition of a substance that preferentially adsorbs moisture, protection the entire API. E.g. silicon dioxide, or silica can be used as such a substance. Types of silica are known that are approved for use
in the pharmaceutical industry. An addition of such silica supported stability of the amorphous form of sofosbuvir even further and higher stability against climatic influences was registered. The amorphous samples of sofosbuvir obtained by means of extrusionwere prepared with the use of a HAAKE™ MiniLab II double-screw micro-kneader with the chamber volume of 7 ml. The material was dosed manually. The rotational speed of the worms was 120 rpm. Theexperiments were carried out at a chamber temperature of 100 to 120°C.
The amorphous form of sofosbuvir prepared with the use of the method according to this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets. Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. microcrystalline cellulose), binders (e.g. povidone), disintegrants (e.g. crospovidone), lubricants (e.g. magnesium stearate), surfactants etc. These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
To verify the concept, tablets containing the amorphous form of sofosbuvir were produced. The method of wet granulation by ethanol with subsequent fluid drying or the method of direct mixing (direct compression) was used. It was followed by the production of tablets. Examples of the said compositions and the description of the production procedures are included in the experimental part. Subsequent analysis confirmed that no polymorphic change of the active pharmaceutical ingredient (API) had occurred and during the production process the chemical purity of the API had been preserved.
Brief description of the Drawings
Fig. 1: DSC record of the amorphous form of sofosbuvir prepared by spray drying
Fig. 2: DSC record of the amorphous form of sofosbuvir prepared by spray drying and
exposed to the conditions of 25% RH and 40°C for 30 days
Fig. 3: DSC record of the amorphous form of sofosbuvir prepared by spray drying and
exposed to the conditions of 0% RH and 40°C for 30 days
Fig. 4: DSC record of the amorphous form of sofosbuvir prepared by spray drying and
exposed to the conditions of 75% RH and 40°C for 30 days
Fig. 5: DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion
Fig. 6: DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 25% RH and 40°C for 30 days
Fig. 7: DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 0% RH and 40°C for 30 days
Fig. 8: DSC record of the amorphous form of sofosbuvir prepared by hot melt extrusion and exposed to the conditions of 75% RH and 40°C for 30 days
The invention is clarified in a more detailed way using the embodiment examples below. These examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.
The term "laboratory temperature" refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C.
Examples
Example 1
Preparation of amorphous sofosbuvir by spray drying
The amount of 30 g of crystalline sofosbuvir (form 1) was dosed into a 250ml Erlenmeyer flask. This solid substance was dissolved in 200 ml of ethyl acetate, being stirred in a magnetic stirrer at 45°C. The solvent was removed from the obtained solution with the use of a BUCHI B290 laboratory spray drier. Carrier gas flow 50 m3/h, inlet temperature 95°C, outlet temperature 78°C, solution dosage rate 15%, aspirator 100%, condensation loop temperature 0°C. This way, the amount of 22 g of the product (yield 60%) was obtained. DSC record in Fig. 1.
Example 2
Preparation of amorphous sofosbuvir by hot melt extrusion
Sofosbuvir was extruded using a HAAKE™ MiniLab II double-screw micro-kneader in the range of 10 to 150 g. The material was dosed manually. The rotary speed of the worms was 120 rpm. Chamber temperature 100°C. This way, amorphous samples without a crystalline admixture were repeatedly obtained. The product yields varied in the range of 90 to 95%. DSC record in Fig. 5.
Example 3
Formulation example
Sofosbuvir (amorphous form) was granulated by ethanol together with microcrystalline cellulose, crospovidone and povidone. The granulate was dried in a fluid drier and sieved. Prosolv (microcrystalline cellulose with a silica layer), the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 1210 mg/tablet. The cores produced this way showed suitable parameters as abrasion, disintegration and dissolution rate of the active ingredient during analytic tests.
Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used. Example 4
Formulation example
Constituent Quantity (% by weight)
Sofosbuvir amorphous form 40
Microcrystalline cellulose 15
Prosolv SMCC90 26
Povidone K25 5
Crospovidone 10
Si02 2.5
Magnesium stearate 1.5
Sofosbuvir (amorphous form) was granulated by ethanol together with microcrystalline cellulose, crospovidone and povidone. The granulate was dried in a fluid drier and sieved. Prosolv (microcrystalline cellulose with a silica layer), the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 1000 mg/tablet. The cores produced this way showed suitable parameters as abrasion, disintegration and dissolution rate of the active ingredient during analytic tests.
Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used.
Example 5
Formulation example
Sofosbuvir (amorphous form) was granulated by ethanol together with crospovidone and povidone. The granulate was dried in a fluid drier and sieved through a sieve with the mesh size of 0.8 mm. Prosolv (microcrystalline cellulose with a silica layer), microcrystalline cellulose, the rest of crospovidone, silica and magnesium stearate were admixed to the granulate. The tablets were tabletted on a rotary tabletting machine. The weight of the cores was 667 mg tablet. The flow properties of the material met the tabletting parameters. Suitable
disintegration, abrasion and dissolution and stability characteristics of the resulting tablets were also achieved.
Dry granulation (also compaction) was another process that was selected as suitable for processing of sofosbuvir. In this experiment, a similar composition as in the case of wet granulation was used.
List of analytical methods
The records of differential scanning calorimetry (DSC) were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μΐ,) was between 3 and 4 mg and the heating rate was 5°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 200°C at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). As the carrier gas 5.0 N2 was used at the flow of 50 ml/min.
Claims
1. A method for preparing (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran 2- yl)methoxy)-(phenoxy)phosphorylamino)-propanoate - sofosbuvir in an amorphous form, characterized in that it comprises aging of the amorphous form at a temperature of 0 to 90°C in an air environment with relative humidity of 0 to 50% RH for 1 to 90 days.
2. The method in accordance with claim 1, characterized in that the air environment has relative humidity of 0 to 25% RH.
3. The method in accordance with claim 1, characterized in that a temperature of 10 to 60°C is selected.
4. The method in accordance with claims 1 to 3, characterized in that the aging is conducted for 10 to 50 days.
5. The method in accordance with any of the preceding claims, characterized in that it also comprises hot melt extrusion at a temperature in the range of 100 to 140°C.
6. (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4- fluoro-3-hydroxy-4-methyltetrahydrofuran 2-yl)methoxy)-(phenoxy)phosphorylamino)- propanoate - sofosbuvir in an amorphous form, characterized in having a glass transition temperature Tg of at least 50°C.
7. Sofosbuvir in accordance with claim 5, characterized in having a glass transition temperature Tg of at least 60°C.
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Cited By (3)
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CN109467577A (en) * | 2018-12-06 | 2019-03-15 | 南通常佑药业科技有限公司 | A kind of preparation method of Suo Feibuwei crystal form and amorphous products |
WO2019134971A1 (en) * | 2018-01-04 | 2019-07-11 | Sandoz Ag | Encapsulated particles comprising a pharmaceutically active ingredient |
US10738071B2 (en) | 2016-03-17 | 2020-08-11 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
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2016
- 2016-05-05 CZ CZ2016-257A patent/CZ2016257A3/en unknown
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2017
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US10738071B2 (en) | 2016-03-17 | 2020-08-11 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
WO2019134971A1 (en) * | 2018-01-04 | 2019-07-11 | Sandoz Ag | Encapsulated particles comprising a pharmaceutically active ingredient |
CN109467577A (en) * | 2018-12-06 | 2019-03-15 | 南通常佑药业科技有限公司 | A kind of preparation method of Suo Feibuwei crystal form and amorphous products |
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