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Evaluation of Drug Load and Polymer by Using a 96-Well Plate Vacuum Dry System for Amorphous Solid Dispersion Drug Delivery

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Abstract

It is well recognized that poor dissolution rate and solubility of drug candidates are key limiting factors for oral bioavailability. While numerous technologies have been developed to enhance solubility of the drug candidates, poor water solubility continuously remains a challenge for drug delivery. Among those technologies, amorphous solid dispersions (SD) have been successfully employed to enhance both dissolution rate and solubility of poorly water-soluble drugs. This research reports a high-throughput screening technology developed by utilizing a 96-well plate system to identify optimal drug load and polymer using a solvent casting approach. A minimal amount of drug was required to evaluate optimal drug load in three different polymers with respect to solubility improvement and solid-state stability of the amorphous drug–polymer system. Validation of this method was demonstrated with three marketed drugs as well as with one internal compound. Scale up of the internal compound SD by spray drying further confirmed the validity of this method, and its quality was comparable to a larger scale process. Here, we demonstrate that our system is highly efficient, cost-effective, and robust to evaluate the feasibility of spray drying technology to produce amorphous solid dispersions.

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References

  1. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19.

    Article  PubMed  CAS  Google Scholar 

  2. Lipinski CA. Poor aqueous solubility—an industry wide problem in drug discovery. Am Pharm. 2002;5:82–5.

    Google Scholar 

  3. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2002;44:235–49.

    Article  Google Scholar 

  4. Lipinski CA. Physicochemical properties and the discovery of orally active drugs: technical and people issues. Molecular informatics: confronting complexity. Proceedings of the Beilstein-Institut Workshop. Germany: Frankfurt; 2003.

    Google Scholar 

  5. Gardner CR, Walsh CT, Almarsson O. Drugs as materials: valuing physical form in drug discovery. Nat Rev Drug Discov. 2004;3:926–34.

    Article  PubMed  CAS  Google Scholar 

  6. Schroter C. Prioritizing molecules based on physicochemical characteristics. Am Pharm. 2006;9:60–7.

    Article  CAS  Google Scholar 

  7. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.

    Article  PubMed  CAS  Google Scholar 

  8. Anon. November 2006. New drug development. GAO Report to Congress. GAO-07-49.

  9. Ruben AJ, Kiso Y, Freire E. Overcoming roadblocks in lead optimization: a thermodynamic perspective. Chem Biol Drug Des. 2006;67:2–4.

    Article  PubMed  CAS  Google Scholar 

  10. Gao P. Amorphous pharmaceutical solids: characterization, stabilization, and development of marketable formulations of poorly soluble drugs with improved oral absorption. Mol Pharm. 2008;5(6):903–4.

    Article  PubMed  CAS  Google Scholar 

  11. Hageman MJ, Miyake PJ, Stefanski KJ, He X, Rohrs BR, Mackin LA, Kararli TT. Solid state form of celecoxib having enhanced bioavailability. 2001;WO0141536.

  12. Gupta P, Kakumanu VK, Bansal AK. Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective. Pharm Res. 2004;21(10):1762–9.

    Article  PubMed  CAS  Google Scholar 

  13. DiNunzio JC, Miller DA, Yang W, McGinity JW, Williams III RO. Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm. 2008;5(6):968–80.

    Article  PubMed  CAS  Google Scholar 

  14. Lipinski C, Lombardo F, Dominy B, Feeney P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26.

    Article  PubMed  CAS  Google Scholar 

  15. Hancock B, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404.

    Article  PubMed  CAS  Google Scholar 

  16. Imaizumi H. Stability and several physical properties of amorphous and crystalline forms of indomethacin. Chem Pharm Bull(Tokyo). 1980;29:983–7.

    Google Scholar 

  17. Kaushal AM, Gupta P, Bansal AK. Amorphous drug delivery systems: molecular aspects, design and performance. Crit Rev Ther Drug Carrier Syst. 2004;21:133–93.

    Article  PubMed  CAS  Google Scholar 

  18. Patel RC, Masnoon S, Patel MM, Patel NM. Formulation strategies for improving drug solubility using solid dispersions. Pharm Rev. 2009;7(6):1918–5561.

    Google Scholar 

  19. Mansky P, Dai W, Li S, Pollock-Dove C, Daehne K, Dong L, Eichenbaum G. Screening method to identify preclinical liquid and semi-solid formulations for low solubility compounds: miniaturization and automation of solvent casting and dissolution testing. J Pharm Sci. 2007;96(6):1548–63.

    Article  PubMed  CAS  Google Scholar 

  20. Shanbhag A, Rabel S, Nauka E, Casadevall G, Shivanand P, Eichenbaum G, Mansky P. Method for screening of solid dispersion formulations of low-solubility compounds—miniaturization and automation of solvent casting and dissolution testing. Int J Pharm. 2008;351:209–18.

    Article  PubMed  CAS  Google Scholar 

  21. Wenglowsky S, Ren L, Ahrendt KA, Laird ER, Aliagas I, Alicke B, Buckmelter AJ, Choo EF, Dinkel V, Feng B, Gloor SL, Gould SE, Gross S, Gunzner-Toste J, Hansen JD, Hatzivassiliou G, Liu B, Malesky K, Mathieu S, Newhouse B, Raddatz NJ, Ran Y, Rana S, Randolph N, Risom T, Rudolph J, Savage S, Selby LT, Shrag M, Song K, Sturgis HL, Voegtli WC, Wen Z, Willis BS, Woessner RD, Wu W, Young WB, Grina J. Pyrazolopyridine inhibitors of B-RafV600E. Part 1: the development of selective, orally bioavailable, and efficacious inhibitors. ACS Med Chem. 2011;2:342–7.

    Article  CAS  Google Scholar 

  22. Fuji Chemical/APIs & Pharmaceuticals Website: http://www.fujichemical.co.jp/english/medical/spray_dry/solution/detail.html

  23. Bee T, Rahman M. Using polymer technology to enhance bioavailability. Pharm Technol. 2010;34(9):6.

    Google Scholar 

  24. Broman E, Khoo C, Taylor LS. A comparison of alternative polymer excipients and processing methods for making solid dispersions of a poorly water soluble drug. Int J Pharm. 2001;222(1):139–51.

    Article  PubMed  CAS  Google Scholar 

  25. Damian F, Blaton N, Kinget R, Van den Mooter G. Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30. Int J Pharm. 2002;244(1–2):87–98.

    Article  PubMed  CAS  Google Scholar 

  26. Thybo P, Hovgaard L, Lindelov JS, Brask A, Andersen SK. Scaling up the spray drying process from pilot to production scale using an atomized droplet size criterion. Pharm Res. 2008;25(7):1610–20.

    Article  PubMed  CAS  Google Scholar 

  27. De Villiers MM, Wuster DE, Van der Watt JG, Ketkar A. X-Ray powder diffraction determination of the relative amount of crystalline acetaminophen in solid dispersions with polyvinylpyrrolidone. Int J Pharm. 1998;163(1–2):219–24.

    Article  Google Scholar 

  28. Gong HK, Viboonkiat R, Rehman IU, Buckton G, Darr JA. Formation and characterization of porous indomethacin-PVP coprecipitates prepared using solvent-free supercritical fluid processing. J Pharm Sci. 2005;94(12):2583–90.

    Article  PubMed  CAS  Google Scholar 

  29. Corrigan OI, Holohan EM, Reilly MR. Physicochemical properties of indomethacin and related compounds co-spray dried with polyvinyl-pyrrolidone. Drug Dev Ind Pharm. 1985;11(2&3):677–95.

    Article  CAS  Google Scholar 

  30. Appel LE, Friesen DT, Herbig SM, Ketner RJ, Shamblin SL. Dosage Forms Comprising celecoxib providing both rapid and sustained pain relief. Patent application number: 20100233272. 2010.

  31. Vasanthavada M, Tong W, Joshi Y, Kislalioglu MS. Phase behavior of amorphous molecular dispersions II: role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm Res. 2005;22(3):440–8.

    Article  PubMed  CAS  Google Scholar 

  32. Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–31.

    Article  PubMed  CAS  Google Scholar 

  33. Neirinckx E, Vervaet C, De Boever S, Remon JP, Gommeren K, Daminet S, De Backer P, Croubels S. Species comparison of oral bioavailability, first-pass metabolism and pharmacokinetics of acetaminophen. Res Vet Sci. 2010;89(1):113–9.

    Article  PubMed  CAS  Google Scholar 

  34. Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky SA, Barends DM. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol). J Pharm Sci. 2006;95(1):4–14.

    Article  PubMed  CAS  Google Scholar 

  35. Yoshioka M, Hancock BC, Zografi G. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J Pharm Sci. 1995;84(8):983–6.

    Article  PubMed  CAS  Google Scholar 

  36. Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14(12):1691–8.

    Article  PubMed  CAS  Google Scholar 

  37. Rumondor AC, Marsac PJ, Stanford LA, Taylor LS. Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm. 2009;6(5):1492–505.

    Article  PubMed  CAS  Google Scholar 

  38. Al-Obaidi H, Brocchini S, Buckton G. Anomalous properties of spray dried solid dispersions. J Pharm Sci. 2009;98(12):4724–37.

    Article  PubMed  CAS  Google Scholar 

  39. Al-Obaidi H, Buckton G. Evaluation of griseofulvin binary and ternary solid dispersions with HPMCAS. AAPS PharmSciTech. 2009;10(4):1172–7.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

Authors thank Array BioPharma (Boulder, CO) and Genentech Chemists which provided compound A.

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Correspondence to Po-Chang Chiang.

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Chiang, PC., Ran, Y., Chou, KJ. et al. Evaluation of Drug Load and Polymer by Using a 96-Well Plate Vacuum Dry System for Amorphous Solid Dispersion Drug Delivery. AAPS PharmSciTech 13, 713–722 (2012). https://doi.org/10.1208/s12249-012-9795-2

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  • DOI: https://doi.org/10.1208/s12249-012-9795-2

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