Abstract
Low-solubility compounds comprise nearly one third of all active pharmaceutical ingredients (APIs) in early development, and up to 70 % of oncology and anti-infective compounds. Spray-dried dispersions (SDDs) of low-solubility compounds using hydroxypropyl methylcellulose acetate succinate (HPMCAS) have proven particularly effective at enhancing oral bioavailability. They do so by (1) enhancing solubilized drug levels compared with crystalline drug, (2) enhancing the dissolution rate compared with crystalline drug, and (3) sustaining enhanced solubilized drug levels in intestinal milieu for a physiologically relevant time.
HPMCAS also has properties that promote solid-state kinetic stabilization of SDDs. These properties include: (1) a heterogeneous distribution of functional groups that interact with a broad range of chemical moieties; (2) a high glass transition temperature (T g), which limits mobility and stabilizes amorphous drug; and (3) relative hydrophobicity, which limits plasticization of the SDD when stored at high relative humidity (RH) or in the presence of residual solvent from the spray-drying process.
Spray drying has proven to be a robust and scalable method (from milligrams to metric tons) to manufacture drug/polymer dispersions from early formulation screening through commercial manufacture. Spray drying from an organic solution enables rapid drying kinetics, which can be critical for preparing homogeneous amorphous dispersions of drug and HPMCAS. The resulting SDDs have routinely exhibited excellent physical stability.
This chapter describes SDDs as a platform technology to enhance oral bioavailability of poorly soluble compounds and covers formulation and process-selection specification, and in vitro performance utilizing HPMCAS-based polymers.
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Notes
- 1.
HPMCAS is also known as hypromellose acetate succinate and is commercially available from Shin-Etsu Chemical Company and The Dow Chemical Company.
- 2.
Numbers are much higher for global testing experience.
- 3.
The enhancement over bulk crystalline drug is lower in cases where the crystalline drug control is moderately well absorbed.
- 4.
The actual rate of phase separation and the corresponding time to 5 % phase separation has been measured for 17 different SDDs over a wide range of storage temperatures—both above and below the T g of the SDD. Based on linear extrapolation of the data for temperatures near or above the T g (plotted as the log10 of the time to 5 % phase separation versus T g/T storage), SDDs should be stable for at least 2 years if stored at temperatures from 5 °C to 33 °C below the T g of the SDD. This prediction is based on data from HPMCAS SDDs for seven different active compounds.
References
Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413–420
Angell CA (1985) Strong and fragile liquids in relaxations in complex systems. In: Nagai K, Wright GB (eds) National Technical Information Service, US Department of Commerce, p 1
Babcock WC, Friesen DT, McCray SB (2009) Method and device for evaluation of pharmaceutical compositions. U.S. Patent No.7,611,630 B2
Chiou WL, Riegelman S (1969) Preparation and dissolution characteristics of several fast-release solid dispersions of griseofulvin. J Pharm Sci 58:1505–1510
Chiou WL, Riegelman S (1970) Oral absorption of griseofulvin in dogs: increased absorption via solid dispersion in polyethyleneglycol 6000. J Pharm Sci 59:937–942
Chiou WL, Riegelman S (1971) Pharmaceutical applications of solid dispersion systems. J Pharm Sci 60:1281–1302
Curatolo W, Nightingale J, Herbig S (2009) Utility of hydroxypropyl methylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res 26(6):1419–1431
Dobry DE, Settell DM, Baumann JM, Ray RJ, Graham LJ, Beyerinck RA (2009) A model-based methodology for spray-drying process development. J Pharm Innov 4(3):133–142
Friesen DT, Shanker R, Crew MD, Smithey DT, Curatolo WJ, Nightingale JAS (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5(6):1003–1019
Goldberg AH, Gibaldi M, Kanig JL (1965) Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures I–theoretical considerations and discussions of the literature. J Pharm Sci 54:1145–1148
Goldberg AH, Gibaldi M, Kanig JL (1966) Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures II– experimental evaluation of a eutectic mixture: urea-acetaminophen system. J Pharm Sci 55:482–487
Government Accounting Office (GAO) (2006) Report to congress, new drug development, GAO-07-49
Higuchi T, Kuramoto R (1954) Study of possible complex formation between macromolecules and certain pharmaceuticals. J Amer Pharm Assn Sci Ed 47:393–397
Horn D, Ditter W (1982) Chromatographic study of interactions between polyvinylpyrrolidone and drugs. J Pharm Sci 71:1021–1026
Leuner C, Dressman J (2000) Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50:47–60
Morgen M, Lyon D, Schmitt R, Brackhagen M, Petermann O (2013) New excipients for solubilizing APIs: expansion of the HPMCAS chemistry space. Tablets Capsul 11(5):10–16
Mathias NR, Xu Y, Patel D, Grass M, Caldwell B, Jager C, Mullin J, Hansen L, Crison J, Saari A, Gesenberg C, Morrison J, Vig B, Raghavan K (2013) Assessing the risk of pH-Dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy. Mol Pharm 10(11):4063–4073. doi: 10.1021/mp400426f
National Formulary (NF) (2006) Official monograph for hypromellose acetate succinate, NF 25, pp 1136–1138
Sekiguchi K, Obi N (1961) Studies on absorption of eutectic mixtures. I. A comparison of the behavior of eutectic mixtures of sulphathiazole and that of ordinary sulphathiazole in man. Clin Pharm Bull 9:866–872
Serajuddin A (1999) Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066
Simonelli AP, Mehta SC, Higuchi WI (1976). Dissolution rates of high energy sulfathiazole-povidone coprecipitates II–characterization of form of drug controlling its dissolution rate via solubility studies. J Pharm Sci 65:355–361
Stoll RT, Bates TR, Nieforth KA, Swarbrick J (1969) Some physical factors affecting the enhanced blepharoptotic activity of orally administered reserpine-cholanic acid coprecipitates. J Pharm Sci 58:1457–1459
Stoll R, Bates T, Swarbrick J (1973) In vitro dissolution and in vivo absorption of nitrofurantoin from deoxycholic acid coprecipitates. J Pharm Sci 62:65–68
US Food and Drug Administration (2008) International conference on harmonisation (ICH)–draft guidance: Q8(R1) pharmaceutical development revision 1. US FDA; Rockville, Maryland
Vodak DT (2013) Development of amorphous solid dispersions using the spray-drying process. Presentation at the 15th international workshop on physical characterization of pharmaceutical solids (IWPCPS®-15), Philadelphia, Pennsylvania, 24–27 June 2013
Wang L, Velikov V, Angell CA (2002) Direct determination of kinetic fragility indices of glass-forming liquids by differential scanning calorimetry. J Chem Phys 117(22):10184–10192
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Vodak, D., Morgen, M. (2014). Design and Development of HPMCAS-Based Spray-Dried Dispersions. In: Shah, N., Sandhu, H., Choi, D., Chokshi, H., Malick, A. (eds) Amorphous Solid Dispersions. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1598-9_9
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