Patent Application
20230414515
The invention discloses a method for preparation of spray dried solid dispersions, SDD, comprising an active agent, AA, such as an active pharmaceutical ingredient, API, and a dispersion polymer, DISPPOL, wherein the spray drying is done with a solution of AA and of DISPPOL in a solvent comprising C1-3 alkanol and acetic acid, and optionally water.
Spray dried solid dispersions, SDD, comprising an active pharmaceutical ingredient, API, and a dispersion polymer, DISPPOL, are typically produced by dissolving the dispersion polymer and the API in a volatile solvent, such as methanol or acetone, or in a mixture of solvents, followed by spray drying. In cases where the API has limited solubility, e.g. <1 wt %, in the spray drying solvent, an API suspension can be heated to a temperature either below or above the solvent's ambient pressure boiling point, this is known as “hot spray drying process”, resulting in a higher dissolved concentration of API. In some cases, even the higher temperatures do not give adequate API concentrations that are economical for a spray drying process, or cause other problems such as chemical degradation of the API, or bear the risk of incomplete API dissolution in the heat exchanger. Alternate, non-preferred volatile solvents can provide increased solubility of the API, but these solvents have other disadvantages that make them less desirable, e.g. high cost, toxicity, poor equipment compatibility, poor commercial availability, high disposal costs, challenges removing to sufficiently low levels, higher viscosity.
WO 2019/220282 A1 discloses in Example 1 spray drying of a solution of erlotinib and a dispersion polymer (PMMAMA or hydroxypropyl methylcellulose acetate succinate H grade) in methanol to provide a spray dried dispersion. The presence of an acid in the spray solution is not mentioned.
WO 2007/060384 A2 discloses in example 4 spray-drying of salbutamol sulphate. Example 4 does not disclose the spray solvent, contrary to examples 2 and 3 which refer to example 1. But assuming that the spray solvent of example 1 was also used in example 4, then the spray solvent contained ca. 550 ml+33 ml=583 ml water and 30 ml EtOH, that is 95 wt % water. Since the sulphate of salbutamol was used for spray drying, the free base form of the drug is not obtained after spray drying, but again the sulphate.
Also example 11 discloses spray-drying of salbutamol sulphate, so again the sulphate is contained in the SDD, not its free base form. 1 ml+ca. 49 ml=50 ml water and ca. 21 ml, that are ca. 17 g of EtOH, assuming the described dilution to 100 ml with aqueous ethanol (30% v/v) needed ca. 70 ml of the aqueous ethanol. So the respective total content of water in the w/o/w emulsion was ca. 75 wt % water based on the combined amount of water and ethanol.
CN110037990A discloses solid amorphous dispersions of apixaban. Apixaban has two pKa values, one acidic pKa of ca. 13 at which half of the acidic site is deprotonated, and a basic pKa of <2 at which half of the respective basic site is protonated (source: https://go.drugbank.com/drugs/DB06605). A combination of THF and acetic acid is used as solvent, ethanol is mentioned only for providing low solubility for apixaban.
WO 2015/138837 A1 discloses amorphous solid dispersions of ivosidenib. Ivosidenib has a basic pKa of ca. 1.81 (https://go.drugbank.com/drugs/DB14568). Only one example of spray drying is disclosed, no acid was contained in the spray mixture.
US 2007/0218012 A1 discloses in the examples methylene chloride and acetone as spray solvents for preparing sold dispersion of VX-950, Telaprevir, which has a basic pKa of −0.69 (https://go.drugbank.com/drugs/DB05521).
WO 2013/105894 A1 discloses the preparation of stable, amorphous hybrid nanoparticles with various protein kinase inhibitors PKI. Solvents used are DMSO, acetone and trifluoroethanol (TFE). A solution of PKI and polymer in said solvents is pumped through XSpray's RightSize nozzle together with a CO2 stream, which method is different from conventional spray drying of a spray solution.
Neither C1-3 alkanols nor acetic acids are mentioned.
There was a need for a method for preparing spray dried solid dispersion of an active agent, AA, which is a weak organic base in its free base form, and dispersion polymers, which allows for dissolving the APIs in easily processable spray drying solvents such as C1-3 alkanols at modest temperature, i.e. a temperature below the ambient pressure boiling point, at sufficiently high concentrations to enable economical throughput of SDDs. By the method the free base should be obtained as a SDD.
It was found that acetic acid may be used as processing aid in such spray drying method. The solubility of the AA is increased, which allows for higher concentration of AA in the spray solution than in absence of acetic acid. Increased AA solubility gives higher manufacturing throughput, and potentially better spray dried particle characteristics than what is achievable with lower solids content spray solutions. When acetic acid is used not only as a processing aid, but as the only solvent then viscosities tend to be high.
Subject of the invention is a method SPRAYDRY for preparing a spray dried solid dispersion, SDD, of an active agent, AA, which is an organic Bronstedt base, comprising:
SDD is a spray dried solid dispersion of AA in DISPPOL. AA and DISPPOL are preferably homogeneously mixed in SDD.
In a solid dispersion of AA in DISPPOL, AA may be homogeneously and preferably also molecularly dispersed in DISPPOL. AA and DISPPOL may form a solid solution in SDD. AA may be amorphous or substantially amorphous in SDD; substantially means that at least 80 wt %, preferably at least 90 wt %, more preferably at least 95 wt %, even more preferably at least 98 wt %, especially at least 99% wt %, of AA is amorphous; the wt % being based on the total weight of AA in SDD. SDD therefore may be an amorphous SDD. The amorphous nature of AA may be evidenced by a lack of sharp Bragg diffraction peaks in the x-ray pattern when SDD is analyzed by a powder X-Ray Diffraction, PXRD. Possible parameters and settings for a x-ray diffractometer are equipment with a Cu-Kalpha source, setting in modified parallel beam geometry between 3 and 40° 2Theta and a scan rate of 2°/min with a 0.0° step size. Another evidence for the amorphous nature of AA in the SDD may be a single glass transition temperature, Tg. A single Tg is also evidence of a homogeneous mixture of amorphous AA and polymer. Samples as such without any further sample preparation may be used for the determination of the Tg, the determination may run for example in modulated mode at a scan rate of 2.5° C./min, modulation of ±1.5° C./min, and a scan range from 0 to 180° C. Amorphous nature of AA shows a Tg which is equal to the Tg of neat DSISPPOL or which is between the Tg of the polymer and the Tg of the AA. The Tg of the SDD is often similar to the weighted average of the Tg of AA and the Tg of DISPPOL. SDD is amorphous or substantially, SDD can also be called ASD.
SPRAYSOL is a stable solution of AA in SOLV and acetic acid.
SPRAYSOL has only one liquid phase. This means that the liquid phase of SPRAYSOL has not more than one liquid phase but is has only one liquid phase, so for example it has not 2 or 3 separate liquid phases, which would be the case if a liquid phase would be a water/oil or water/oil/water emulsion or the like.
The amount of AA with respect to SOLV is above the solubility of AA in SOLV in absence of acetic acid.
The amount of acetic acid is sufficient to solubilize AA in SOLV.
The amount of acetic acid may be 1 to 50 eq, preferably 1 to 40 eq, more preferably 1 to 30 eq, even more preferably 1 to 25 eq, based on the molar amount of AA.
The amount of acetic acid may be up to 50 wt %, preferably up to 40 wt %, more preferably up to 30 wt %, even more preferably up to 25 wt %, especially up to 15 wt %, more especially up to 10 wt %, even more especially up to 7.5, in particular up to 5 wt %, the wt % being based on the weight of SOLV.
The amount of acetic acid may be from 0.05 to 50 wt %, preferably from 0.05 to 40 wt %, more preferably from 0.05 to 30 wt %, even more preferably from 0.05 to 25 wt %, especially from 0.05 to 15 wt %, more especially from 0.1 to 10 wt %, even more especially from 0.1 to 7.5, in particular from 0.1 to 5 wt %, the wt % being based on the weight of SOLV.
The C1-3 alkanol of SOLV may be methanol, ethanol or isopropanol, preferably methanol or ethanol, more preferably methanol.
The amount of the C1-3 alkanol in SOLV may be at least 60 wt %, or at least 65 wt %, or at least 67.5 wt %, or at least 70 wt %, or at least 75 wt %, or at least 80 wt %, or at least 85 wt %, or at least 90 wt %, or at least 95 wt %; with the wt % being based on the weight of SOLV.
In another embodiment, SOLV may further comprise water.
When SOLV comprises water, then SOLV comprises not more than 40 wt %, preferably not more than 35 wt %, more preferably not more than 32.5 wt %, even more preferably not more than 30 wt %, especially not more than 25 wt %, more especially not more than 20 wt %, of water, with the wt % being based on the combined weights of C1-3 alkanol and water. When SOLV comprises water, then the weight ratio C1-3 alkanol:water in SOLV may be from 99:1 to 60:40, preferably from 99:1 to 65:35, more preferably from 99:1 to 67.5:32.5, even more preferably from 99:1 to 70:30, especially from 99:1 to 75:25, more especially from 99:1 to 80:20.
In one embodiment, SOLV consists of C1-3 alkanol and water.
In one embodiment, SOLV consists of C1-3 alkanol.
AA is in its free base form when combined with or added to the acetic acid and SOLV to form SPRAYSOL.
AA may be present in SPRAYSOL in its free base form, in its protonated form or in both forms, depending on its basic pKa.
The SDD may comprise from 1 to 99 wt %, preferably from 10 to 95 wt %, more preferably from 10 to 80 wt %, even more preferably from 20 to 60 wt %, of AA, the wt % being based on the weight of the SDD.
The SDD may comprise from 1 to 99 wt %, preferably from 20 to 90 wt %, more preferably from 40 to 80 wt %, of DISPPOL, the wt % being based on the weight of the SDD.
Preferably, the combined content of AA and DISPPOL in SDD is from 65 to 100 wt %, more preferably from 67.5 to 100 wt %, even more preferably from 80 to 100 wt %; especially from 90 to 100 wt %; more especially from 95 to 100 wt %;
Relative amounts of AA to DISPPOL in SDD may be from 50:1 to 1:50, preferably from 25:1 to 1:25, more preferably from 10:1 to 1:10 (w/w).
Amounts of DISPPOL and of AA in SPRAYSOL are chosen such that a predefined amount of DISPPOL and of AA in SDD provided.
For example amounts of DISPPOL in SPRAYSOL may be from 0.5 wt % to 20 wt %, preferably from 1 wt % to 20 wt %, more preferably from 2.5 wt % to 15 wt %, even more preferably from 5 wt % to 10 wt %, with the wt % being based on the weight of SPRAYSOL.
Preferably, AA may have a solubility of 30 mg/mL or less, more preferably of 20 mg/mL or less, even more preferably of 10 mg/mL or less, in SOLV.
AA is an organic Bronstedt base.
In some embodiments, DISPPOL is HPMCAS or PMMAMAA.
SPRAYSOL may be fed into the spray dryer with a temperature of SPRAYSOL up to the boiling point of SPRAYSOL at ambient pressure; preferably with a temperature of from 4° C. to the boiling point of SPRAYSOL at ambient pressure, preferably from 4° C. to a temperature below the boiling point of SPRAYSOL at ambient pressure, more preferably from room temperature to 60° C. In the context of this invention the term “SPRAYSOL may be fed into the spray dryer with a temperature of SPRAYSOL” means that “SPRAYSOL is spray dried with a temperature of SPRAYSOL”.
The spray drying may be done with an inlet temperature of from 60 to 165° C.
The spray drying may be done with an outlet temperature equal to or less than the boiling point of SOLV.
The spray drying may be done with any inert gas commonly used for spray drying, such as nitrogen.
The spray drying does preferably not use CO2 for dissolving or solubilizing AA. CO2 is preferably not added to or mixed with SPRAYSOL. CO2 is preferably not mixed with SPRAYSOL in the nozzle of the spray dryer. When CO2 is used in the spray drying then it may be used in the conventional way as conventional inert drying gas in the spray drying process.
SPRAYSOL may further comprises a dissolved surfactant SURF.
SURF may be mixed with SPRAYSOL.
SURF may be for example a fatty acid and alkyl sulfonate, docusate sodium (for example available from Mallinckrodt Spec. Chem., St. Louis, Mo.), polyoxyethylene sorbitan fatty acid esters (for example Tween®, available from ICI Americas Inc, Wilmington, Del., or Liposorb® P-20, available from Lipochem Inc, Patterson, N.J., or Capmul® POE-0, available from Abitec Corp., Janesville, Wis.), natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, other phospholipids and mono- and diglycerides, vitamin E TPGS, PEO-PPO-PEO triblock copolymers (for example known under the tradename pluronics), or PEO (PEO are also called PEG, polyethyleneglycols (PEG)).
The amount of SURF may be up to 10 wt %, the wt % being based on the weight of SDD.
SPRAYSOL may further comprises pharmaceutically acceptable excipients, such as fillers, disintegrating agents, pigments, binders, lubricants, flavorants, and so forth which can be used for customary purposes and in typical amounts known to the person skilled on the art.
The SDD may comprise residual acetic acid, preferably in low amounts; the content of residual acetic acid in SDD may be 5′000 ppm or less, preferably 500 ppm or less, more preferably of 100 ppm or less, the ppm being based on the weight of SDD.
Also after the spraying any content of residual acetic acid in SDD may be lowered to a predefined content of residual acetic acid, this may be done with an additional drying step after spray drying.
The SDD may comprise residual SOLV, the content of residual SOLV in SDD may be 5′000 ppm or less, preferably 3′000 ppm or less, more preferably 500 ppm or less, even more preferably of 100 ppm or less, the ppm being based on the weight of SDD.
Also after the spraying any content of residual SOLV in SDD may be lowered to a predefined content of residual SOLV in SD.
Any residual content of acetic acid or of SOLV in SDD may be reduced to the desired predefined and final content by submitting SDD after the spray drying to a second drying. Secondary drying may be done using a tray dryer or any agitated dryer known to the skilled person for drying solids.
Dasatinib free base was recrystallized from methanol and dried. Crystalline dasatinib was added in excess to methanol to form a saturated solution at 25° C. The solution was analyzed by TGA and found to contain 3.1 mg/mL dasatinib.
200 mg of crystalline dasatinib was slurried in 10 mL of methanol at 25° C. The slurry was titrated with glacial acetic in 100 microliter increments until the dasatinib was completely dissolved. After a total of 500 microliter (21.5 eq based on the molar amount of dasatinib) of glacial acetic acid was added the mixture became clear. The concentration of dissolved dasatinib was approximately 19 mg/mL and ca. 6 fold higher than in methanol without acetic acid that was used in example 1.
HPMCAS-MG polymer, 7.51 g, was dissolved in 98.2 g of methanol at 19° C. Crystalline dasatinib free base, 2.50 g was added forming a slurry. Glacial acetic acid, 6.5 g (21 eq based on the molar amount of dasatinib), was added with stirring and placed in a 25° C. water bath for 1 hour converting the slurry into a solution with 8.7 wt % dissolved solids. The solution was removed from the water bath, allowed to cool for 30 min to 19° C. and then spray-dried. The solution did not contain dasatinib in solid form, instead it contained the dasatinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using a custom built lab-scale spray dryer. The solution was pumped into a lab-scale 0.3 m diameter stainless steel spray drying chamber using a peristaltic pump. The flow rate of the solution was 20 g/min., atomization was done through a two-fluid nozzle ¼ J series with an 1650 liquid body and 64 air cap made by Spraying Systems Company, Glendale Heights, IL 60187-7901, US. Sheath gas was used to atomize the solution at a pressure of 15 psi. Heated nitrogen gas was introduced into the spray chamber at a temperature of 115 to 120° C. and flow rate of 500 g/min. The outlet temperature of the gas exiting the chamber was 45 to 50° C. The resulting SDD was collected using a cyclone to separate the solid particles from the gas stream.
Residual acetic acid was removed by drying on a tray dryer at 60° C. and 30% RH for 8 h. The residual acetic acid was measured to be 230 ppm by GC. The residual methanol was measured to be below 100 ppm by GC. PXRD shows a homogeneous amorphous solid dispersion.
Eudragit L-100 (PMMAMAA) polymer, 7.50 g, was dissolved in 98.4 g of methanol at 19° C. Crystalline dasatinib free base, 2.51 g, was added forming a slurry. Glacial acetic acid, 6.5 g (21 eq based on the molar amount of dasatinib), was added with stirring and placed in a 25° C. water bath for 30 min converting the slurry into a solution with 8.7 wt % dissolved solids. The solution was removed from the water bath, allowed to cool for 30 min to 19° C. and then spray-dried.
The solution did not contain dasatinib in solid form, instead it contained the dasatinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using a custom built lab-scale spray dryer. The solution was pumped into a lab-scale 0.3 m diameter stainless steel spray drying chamber using a peristaltic pump. The flow rate of the solution was 20 g/min., atomization was done through a two-fluid nozzle ¼ J series with an 1650 liquid body and 64 air cap made by Spraying Systems Company, Glendale Heights, IL 60187-7901, United States. Sheath gas was used to atomize the solution at a pressure of 15 psi. Heated nitrogen gas was introduced into the spray chamber at a temperature of 115 to 120° C. and flow rate of 500 g/min. The outlet temperature of the gas exiting the chamber was 45 to 50° C. The resulting SDD was collected using a cyclone to separate the solid particles from the gas stream.
Residual acetic acid was removed by drying on a tray dryer at 60° C. and 30% RH for 24 h. The residual acetic acid was measured to be 5′000 ppm by GC. The residual methanol was measured to be below 100 ppm by GC. PXRD shows a homogeneous amorphous solid dispersion.
Crystalline gefitinib was added in excess to methanol and methanol:water mixtures to form saturated solutions at 20° C. After 24 hour of stirring, 1 mL aliquots were centrifuged at 10′000 RCF for 3 min. The supernatant was then analyzed for gefitinib concentration by HPLC.
The solubility of gefitinib in solvent mixtures with acetic acid were obtained by suspending 300 mg of crystalline gefitinib in 5 mL of solvent (methanol:water) containing 150 microliters of acetic acid at 20° C. (3.9 eq of acetic acid). With the exception of 100% methanol, all solutions were visually soluble at 60 mg/mL. The solubility in 100% methanol with acetic acid was determined after separating undissolved solids by centrifugation of a 1 mL aliquot at 10′000 RCF for 3 min after 1 hour of stirring. The supernatant was then analyzed for gefitinib concentration by HPLC.
Table 1 shows the gefitinib solubility enhancement in solvent mixtures using 3.9 eq of acetic acid; the enhancement is expressed in Table 1 in form of an Enhancement Factor which is the ratio of
Table 2 shows the spray solution compositions for examples 6 to 9
A slurry was made by first dissolving 9 g of HPMCAS-MG in a mixture of 98 g of methanol and 18.7 g water at 22° C., and then adding 3 g of crystalline gefitinib to form a drug slurry. To this slurry was added 11 mL of 0.075 g/mL glacial acetic acid in methanol. The mixture was stirred for at least 30 min to dissolve the drug and thereby to form a solution SPRAYSOLV.
SPRAYSOLV did not contain gefitinib in solid form, instead it contained the gefitinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using a custom built spray dryer. The solution was pumped into a lab-scale 0.3 m diameter stainless steel spray drying chamber using a peristaltic pump at a solution flow rate of 15 g/min. The spray solution was atomized using a two-fluid ¼ J series nozzle with a 1650 liquid body and 64 air cap (Spraying Systems Company, Glendale Heights, IL 60187-7901, US). Room temperature sheath gas (15 to 20 psi) was used to atomize the solution and heated nitrogen gas (115 to 125° C. inlet, 45 to 50° C. outlet, 500 g/min) was used to dry the particles. The resulting SDD was collected using a cyclone to separate the solid particles from the gas stream.
Samples were placed in a tray dryer at two conditions: 40° C./15% RH and 60° C./30% RH. Methanol was measured by GC to be <100 ppm after 1 h at both conditions, and acetic acid was measured to be <500 ppm after 8 h at 40° C./15% RH and after 1 h at 60° C./30% RH.
PXRD showed the spray dried material to be amorphous.
A slurry was made by first dissolving 9 g of HPMCAS-MG in a mixture of 83.1 g of methanol and 39.1 g water at 22° C., and then adding 3 g of crystalline gefitinib to form a drug slurry. To this slurry was added 11 mL of 0.075 g/mL glacial acetic acid in methanol. The mixture was stirred for at least 30 minutes to dissolve the drug. The mixture was stirred for at least 30 min to dissolve the drug and thereby to form a solution SPRAYSOLV.
SPRAYSOLV did not contain gefitinib in solid form, instead it contained the gefitinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using the procedure of Example 6.
Samples were placed in a tray dryer at two conditions: 40° C./15% RH and 60° C./30% RH. Methanol was measured by GC to be <100 ppm after 1 h at both conditions, and acetic acid is measured to be <500 ppm at after 8 h at 40° C./15% RH and after 1 hour at 60° C./30% RH. PXRD showed the spray dried material to be amorphous.
A slurry was made by first dissolving 9 g of HPMC E3 in a mixture of 51.1 g of methanol and g water at 22° C., adding an additional 42.3 g methanol after the HPMC E3 was dissolved, then adding 3 g of crystalline gefitinib. To this slurry was added 10 mL of 0.075 g/mL glacial acetic acid in methanol. The mixture was stirred for at least 30 min to dissolve the drug and thereby to form a solution SPRAYSOLV.
SPRAYSOLV did not contain gefitinib in solid form, instead it contained the gefitinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using the procedure of Example 6.
Samples were placed in a tray dryer at two conditions: 40° C./15% RH and 60° C./30% RH. Methanol was measured by GC to be <100 ppm after 1 h at both conditions, and acetic acid is measured to be <500 ppm at after 24 h at 40° C./15% RH and after 2 h at 60° C./30% RH. PXRD showed the spray dried material to be amorphous.
A slurry was made by first dissolving 9 g of PVP-VA64 in a mixture of 98 g of methanol and 18.6 g water at 22° C., and then adding 3 g of crystalline gefitinib to form a drug slurry. To this slurry was added 11 mL of 0.075 g/mL glacial acetic acid in methanol. The mixture was stirred for at least 30 min to dissolve the drug and thereby to form a solution SPRAYSOLV. SPRAYSOLV did not contain gefitinib in solid form, instead it contained the gefitinib in a completely dissolved state, and it had only one liquid phase.
The solution was spray dried using the procedure of Example 6.
Samples were placed in a tray dryer at two conditions: 40° C./15% RH and 60° C./30% RH. Methanol was measured by GC to be <100 ppm after 1 h at both conditions, and acetic acid is measured to be <500 ppm at after 24 h at 40° C./15% RH and after 4 h at 60° C./30% RH. PXRD showed the spray dried material to be amorphous.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20200895.9 | Oct 2020 | EP | regional |
| 20208785.4 | Nov 2020 | EP | regional |
| 21150829.6 | Jan 2021 | EP | regional |
| 21177685.1 | Jun 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/076996 | 9/30/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63086691 | Oct 2020 | US |
