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CA-3242913-C - A METHOD FOR CRYSTALLIZATION OF ACTIVE PHARMACEUTICAL INGREDIENTS

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Abstract

The disclosure relates to methods for crystallization of active pharmaceutical ingredients (APIs), wherein the crystallization and crystal growth is controlled. According to the method solid amorphous nanosized API and an aqueous solution comprising one or more polymers and/or copolymers are contacted so as to form a suspension comprising nanosized API in crystalline form.

Inventors

  • Eric Kissi
  • Nikolay Houbenov
  • Tatiana Danilova
  • Niklas Sandler
  • Martti KAASALAINEN

Assignees

  • NANOFORM FINLAND OYJ

Dates

Publication Date
20260505
Application Date
20240118
Priority Date
20230118

Claims (20)

  1. 21 WHAT IS CLAIMED IS 1. A method for crystallization of active pharmaceutical ingredient (API), the method comprising - providing an amorphous nanosized API; - providing an aqueous solution comprising one or more polymers and/or copolymers; and - contacting the amorphous nanosized API and the aqueous solution comprising the one or more polymers and/or copolymers to form an admixture, wherein a content of the amorphous nanosized API in the admixture is higher than the solubility of the amorphous nanosized API in the aqueous solution comprising the one or more polymers and/or copolymers, thereby obtaining a suspension comprising nanosized API in crystalline form.
  2. 2. The method according to claim 1, wherein the content of the amorphous nanosized API in the admixture is at least 10 times higher than the solubility of the amorphous nanosized API in the solution comprising the one or more polymers and/or copolymers.
  3. 3. The method according to claim 2, wherein the content of the amorphous nanosized API in the admixture is at least 50 times higher than the solubility of the amorphous nanosized API in the solution comprising the one or more polymers and/or copolymers.
  4. 4. The method according to any one of claims 1 to 3, wherein the API:polymer and/or copolymer ratio is from 10:1 to 1:10, wherein the content of the API is calculated as mg/mL of the suspension and the content of the polymer is calculated as weight-% of the one or more polymers and/or copolymers of the suspension.
  5. 5. The method according to any one of claims 1 to 4, wherein the aqueous solution comprising one or more polymers and/or copolymers further comprises one of more surfactants. 22
  6. 6. The method according to claim 5, wherein the content of the one or more surfactants in the aqueous solution is 0.0025-1.5% by weight.
  7. 7. The method according to claim 5 or 6, wherein the one or more surfactants are selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS) and tocofersolan (TPGS).
  8. 8. The method according to any one of claims 1 to 7, wherein the one or more polymers are selected from the group consisting of polyvinylpyrrolidone/vinyl acetate (PVPVA), polyvinyl acetate (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), Hypromellose acetate succinate (HPMCAS), polyacrylic acid (PAA), polyethylene glycol (PEG), polyvinyl caprolactam (PVCL), poloxamers, poly(N-vinyl caprolactam)–poly(vinyl acetate)–poly(ethylene glycol) and proteins.
  9. 9. The method according to claim 8, wherein the polymer is PVPVA, and the aqueous solution comprises 0.2-50 wt.-% PVPVA.
  10. 10. The method according to claim 8 wherein the polymer is HPMC, and the aqueous solution comprises 0.2-5 wt.-% HPMC.
  11. 11. The method according to any one of claims 1 to 10, wherein the API is selected from the group consisting of: APIs of BSC Class II and APIs of BSC Class IV.
  12. 12. The method according to any one of claims 1 to 11, wherein the API is selected from the group consisting of adefovir dipivoxil, apalutamide, atazanavir, avacopan, deucravacitinib, doravirine, enzalutamide, elagolix, encorafenib, etravirine, everolimus, etonogestrel, fenofibrate, glecaprevir, pibrentasvir, grazoprevir, pibrentasvir, griseofulvin, telmisartan, itraconazole, ivacaftor, lumacaftor, tezacaftor, elexacaftor, lonafarnib, nabilone, olaparib, paclitaxel, posaconazole, pralsetinib, regorafenib, ripretinib, ritonavir, lopinavir, paritaprevir, ombitasvir, sofosbuvir, ledipasvir, suvorexant, 23 tacrolimus, tadalafil, telaprevir, telmisartan, tolvaptan, vemurafenib, venetoclax, verapamil and any combinations thereof.
  13. 13. The method according to any one of claims 1 to 12, wherein the contacting comprises mixing the suspension.
  14. 14. The method according any one of claims 1 to 13, wherein the contacting comprises subjecting the suspension to ultrasound.
  15. 15. The method according to claim 14, wherein the intensity of the ultrasound is 3 W/cm2 or less.
  16. 16. The method according to any one of claims 1 to 15, wherein the contacting is at least for 10 h.
  17. 17. The method according to any one of claims 1 to 16, further comprising drying the suspension thereby producing a solid comprising the nanosized API in crystalline form and the one or more polymers and/or copolymers.
  18. 18. The method according to claim 17, further comprising crushing the solid thereby producing a powder comprising the nanosized API in crystalline form and the one or more polymers and/or copolymers.
  19. 19. The method according to any one of claims 1 to 18, further comprising isolating the nanosized API in crystalline form from the suspension.
  20. 20. The method according to any one of claims 1 to 19, wherein the particle size of the crystalline API is not more than 300% larger than the particle size of the amorphous nanosized API.

Description

1 A method for crystallization of active pharmaceutical ingredients FIELD The disclosure relates to methods for crystallization of active pharmaceutical ingredients (APIs), in particular to methods wherein the crystallization and crystal growth is controlled by aqueous solutions comprising one or more polymers and/or copolymers. BACKGROUND Many active pharmaceutical ingredients (APIs) show limited bioavailability, mainly due to their inadequate dissolution rate to treat the pathology of interest. It is well known that API dissolution rate depends on the available surface area. API particle size reduction can be used to increase the surface area and the dissolution rate. In addition, nanonization may increase solubility. Accordingly, API size reduction using micronization/nanonization techniques is a valid approach to improve the bioavailability of APIs. It is also known that amorphous materials may have solubilities significantly higher than solubilities of the corresponding crystalline counterparts which would make amorphization an attractive option. Unfortunately, amorphous APIs tend to crystallize during processing, storage and upon administration and thus the solubility advantage may be lost. One of the most commonly used approaches to stabilize the amorphous drugs is to molecularly disperse the drug in a polymeric matrix and form an amorphous solid dispersion (ASD). However, for stabilization an ASD dose must include a significant amount of polymer. EP1347747 discloses a method for preparing sub-micron size API comprising dissolving the API into a water-miscible first solvent to form a solution, mixing the solution into a second solvent comprising surface modifiers to produce a pre¬ suspension, and adding energy to the pre-suspension by homogenization, counter¬ current homogenization, microfluidization or sonication. US2005202092A1 discloses methods for crystallization of API comprising rapid addition of a solution of API in organic solvent to aqueous polymeric solution.5 CA 03242913 2024-7-2 2 US5518738 discloses a method for crystallization of API comprising dispersing amorphous API into a water solution of polyvinyl pyrrolidone (PVP) followed by processing through a media mill filled with polymeric milling media until the mean particle size of the API is ca 200 nm. US20150125535A1 discloses a method for crystallizing coarse API particles by milling in aqueous Pluronic F127 until particle size is reduced to ca 270 nm. Xia et al (Pharm. Res. 2012, 29:158-169) discloses a method for forming crystalline nitrendipine nanoparticles. In the method, nitrendipine is dissolved in a solvent of polyethylene glycol (PEG) and acetone followed by precipitation from an aqueous solution of polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC) or poloxamer. The first particles that were formed were amorphous. When precipitation process continued, these particles converted to nanosized crystals provided that the process is performed at low temperature. However, there is still need for further methods for preparation of active pharmaceutical ingredients of improved bioavailability. SUMMARY The present disclosure is based on the observation that when amorphous nanosized active pharmaceutical ingredients (APIs) were contacted with aqueous solutions comprising one or more polymers and/or copolymers, suspensions comprising nanosized APIs in crystalline form were obtained. Accordingly, it is an object of the present disclosure to provide a new method for crystallization of active pharmaceutical ingredient (API), the method comprising - providing amorphous nanosized API, - providing an aqueous solution comprising one or more polymers and/or copolymers, and - contacting the amorphous nanosized API and the aqueous solution comprising the one or more polymers and/or copolymers to form an admixture so as content of the amorphous nanosized API in the admixture is higher than the solubility of the amorphous nanosized API in the aqueous solution comprising the one or more polymers and/or copolymers thereby obtaining a suspension comprising the nanosized API in crystalline form.5 CA 03242913 2024-7-2 3 Further aspects of the present disclosure are described in the accompanying dependent claims. Exemplifying and non-limiting embodiments of the invention, both as to constructions and to methods of operation, together with additional objects and advantages thereof, are best understood from the following description of specific exemplifying embodiments when read in connection with the accompanying figures. The verbs “to comprise” and “to include” are used in this document as open limitations that neither exclude nor require the existence of unrecited features. The features recited in the accompanied depending claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of "a" or "an", i.e. a singular form, throughout this document does not exclude a plurality. BRIEF DESCRIP