Abstract
The oral bioavailability enhancement of poorly water-soluble medicaments is still one of the most complicated aspects of the formulation development. Various approaches are currently available for solubility and rate of dissolution enhancement such as salt formation, solubilization and reduction of particle size, each with its own limitations and advantages. Solid dispersion is one of the most suitable approaches for the formulation development of poorly water-soluble drugs. The popularity of solid dispersion is evident from the increasing number of patent applications and patents granted in this field during recent years. This article reviews the various approaches for the preparation of solid dispersion such as a solvent melting, hot-melt extrusion method, solvent evaporation method, cryogenic processing approaches etc. from the perspective of patents filed or granted for these techniques. Some of the aspects taken into account before the preparation of solid dispersions are carrier selection and physicchemical testing along with an insight into the molecular arrangement of medicaments in solid dispersion. The manuscript further highlights various commercial patented technology platforms such as Solumertm, Hovione and Kinetisol which are based on the concept of solid dispersions.
Keywords: Solid dispersion, patents, dissolution, bioavailability, solubility, patented platform, carrier.
Graphical Abstract
[1]
Youn YS, Jung JY, Oh SH, Yoo SD, Lee KC. Improved intestinal delivery of salmon calcitonin by Lys18-amine specific PEGylation: Stability, permeability, pharmacokinetic behavior and in vivo hypocalcemic efficacy. J Control Release 2006; 114(3): 334-42.
[http://dx.doi.org/10.1016/j.jconrel.2006.06.007] [PMID: 16884808]
[http://dx.doi.org/10.1016/j.jconrel.2006.06.007] [PMID: 16884808]
[2]
Sugawara M, Singh N. The use of an in vitro dissolution and assimilation system to evaluate oral assimilation of two weak bases in pH-independent controlled-discharge formulations. Eur J Pharm Sci 2005; 26: 1-8.
[http://dx.doi.org/10.1016/j.ejps.2005.02.017] [PMID: 15961297]
[http://dx.doi.org/10.1016/j.ejps.2005.02.017] [PMID: 15961297]
[3]
Vemula VR, Lagishetty V, Lingala S. Solubility enhancement approaches. Int J Pharm Sci Rev Res Dev 2010; 5(1): 41-51.
[4]
Arora SC, Sharma PK. Development, characterization and solubility study of SD of cefixime trihydrate by solvent evaporation method. Int J Drug Dev Res 2010; 2: 424-30.
[5]
Chiou WL, Riegelman S. Preparation and dissolution characteristics of several fast-release solid dispersions of griseofulvin. J Pharm Sci 1969; 58(12): 1505-10.
[http://dx.doi.org/10.1002/jps.2600581218] [PMID: 5353269]
[http://dx.doi.org/10.1002/jps.2600581218] [PMID: 5353269]
[6]
Vasconcelos TF, Sarmento B, Costa P. Solid Dispersion as strategy to improve oral bioavailability of PWS drug. Drug Discov Today 2007; 12: 23-4.
[http://dx.doi.org/10.1016/j.drudis.2007.09.005]
[http://dx.doi.org/10.1016/j.drudis.2007.09.005]
[7]
Sarangi MK, Singh N. Solid Dispersion - a Novel Approach for Enhancement of Bioavailability of Poorly Soluble Drug in Oral Drug Delivery System. Glob J Pharmaceu Sci 2017; 3(2): 22-33.
[8]
Kumar A, Sahoo SK, Padhee K. Review on solubility enhancement approaches for hydrophobic drugs. Int J Comp Pharm 2011; 3: 1-7.
[9]
Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 2000; 50(1): 47-60.
[http://dx.doi.org/10.1016/S0939-6411(00)00076-X] [PMID: 10840192]
[http://dx.doi.org/10.1016/S0939-6411(00)00076-X] [PMID: 10840192]
[10]
Leuner C, Dressman J. Improving drug solubility for oral delivery using SDs. Eur J Pharm Biopharm 2001; 50: 45-50.
[11]
Huang J, Wigent RJ, Schwartz JB. Nifedipine molecular dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blends for controlled drug delivery: effect of matrix composition. Drug Dev Ind Pharm 2006; 32(10): 1185-97.
[http://dx.doi.org/10.1080/03639040600832827] [PMID: 17090441]
[http://dx.doi.org/10.1080/03639040600832827] [PMID: 17090441]
[12]
Desai J, Alexander K, Riga A. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int J Pharm 2006; 308(1-2): 115-23.
[http://dx.doi.org/10.1016/j.ijpharm.2005.10.034] [PMID: 16326055]
[http://dx.doi.org/10.1016/j.ijpharm.2005.10.034] [PMID: 16326055]
[13]
Iqbal Z, Babar A, Ashraf M. Controlled-release naproxen using micronized ethyl cellulose by wet-granulation and solid-dispersion method. Drug Dev Ind Pharm 2002; 28(2): 129-34.
[http://dx.doi.org/10.1081/DDC-120002445] [PMID: 11926356]
[http://dx.doi.org/10.1081/DDC-120002445] [PMID: 11926356]
[14]
Cui F, Yang M, Jiang Y, et al. . Design of sustained-discharge nitrendipine microspheres having SD structure by quasi-emulsion. J Contr Releas 91: 375-84..
[15]
Craig DQ. The mechanisms of drug discharge from SDs in water-soluble polymers. Int J Pharm 2002; 231(1374): 131-44.
[http://dx.doi.org/10.1016/S0378-5173(01)00891-2] [PMID: 11755266]
[http://dx.doi.org/10.1016/S0378-5173(01)00891-2] [PMID: 11755266]
[16]
Okonogi S, Oguchi T, Yonemochi E, Puttipipatkhachorn S, Yamamoto K. Improved dissolution of ofloxacin via SD. Int J Pharm 1997; 156: 175-80.
[http://dx.doi.org/10.1016/S0378-5173(97)00196-8]
[http://dx.doi.org/10.1016/S0378-5173(97)00196-8]
[17]
Majerik V, Charbit G, Badens E, et al. Bioavailability enhancement of an active substance by supercritical antisolvent precipitation. J Supercrit Fluids. 2007; 40: 101–
110.
[http://dx.doi.org/10.1016/j.supflu.2006.03.027]
[http://dx.doi.org/10.1016/j.supflu.2006.03.027]
[18]
Yoshihashi Y, Xenakis B. Estimation of physical stability of amorphous Solid Dispersion using differential scanning calorimetry. J Therm Anal Calorim 2006; 85: 689-92.
[http://dx.doi.org/10.1007/s10973-006-7653-8]
[http://dx.doi.org/10.1007/s10973-006-7653-8]
[19]
Cutler L, Howes C, Deeks NJ, Buck TL, Jeffrey P. Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier. J Pharm Sci 2006; 95(9): 1944-53.
[http://dx.doi.org/10.1002/jps.20658] [PMID: 16850390]
[http://dx.doi.org/10.1002/jps.20658] [PMID: 16850390]
[20]
Serajuddin AT. SD of poorly water-soluble medicaments: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 1999; 88: 1058-66.
[http://dx.doi.org/10.1021/js980403l] [PMID: 10514356]
[http://dx.doi.org/10.1021/js980403l] [PMID: 10514356]
[21]
Karavas E, Ktistis G, Xenakis A, Georgarakis E. Effect of hydrogen bonding interactions on the release mechanism of felodipine from nanodispersions with polyvinylpyrrolidone. Eur J Pharm Biopharm 2006; 63(2): 103-14.
[http://dx.doi.org/10.1016/j.ejpb.2006.01.016] [PMID: 16675209]
[http://dx.doi.org/10.1016/j.ejpb.2006.01.016] [PMID: 16675209]
[22]
Craig DQ. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm 2002; 231(2): 131-44.
[http://dx.doi.org/10.1016/S0378-5173(01)00891-2] [PMID: 11755266]
[http://dx.doi.org/10.1016/S0378-5173(01)00891-2] [PMID: 11755266]
[23]
Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006; 29(3-4): 278-87.
[http://dx.doi.org/10.1016/j.ejps.2006.04.016] [PMID: 16815001]
[http://dx.doi.org/10.1016/j.ejps.2006.04.016] [PMID: 16815001]
[24]
Muhrer G, Meier U, Fusaro F, Albano S, Mazzotti M. Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble medicament: Generation of medicament microparticles and medicament-polymer Solid Dispersion. Int J Pharm 2006; 308: 69-83.
[http://dx.doi.org/10.1016/j.ijpharm.2005.10.026] [PMID: 16324806]
[http://dx.doi.org/10.1016/j.ijpharm.2005.10.026] [PMID: 16324806]
[25]
Pokharkar VB. Development, characterization and stabilization of amorphous form of a low Tg drug. Powder Technol 2006; 167: 20-5.
[http://dx.doi.org/10.1016/j.powtec.2006.05.012]
[http://dx.doi.org/10.1016/j.powtec.2006.05.012]
[26]
Vanden MG, Weuts I, Ridder DT, Blaton N. Evaluation of Inutec SP1 as a new carrier in the formulation of SDs for poorly soluble medicaments. Int J Pharm 2006; 316: 1-6.
[http://dx.doi.org/10.1016/j.ijpharm.2006.02.025] [PMID: 16563676]
[http://dx.doi.org/10.1016/j.ijpharm.2006.02.025] [PMID: 16563676]
[27]
Chauhan B, Shimpi S, Paradkar A. Preparation and evaluation of glibenclamide polyglycolized glycerides SDs with silicon dioxide by spray drying approach. Eur J Pharm Sci 2005; 26: 219-30.
[http://dx.doi.org/10.1016/j.ejps.2005.06.005] [PMID: 16087324]
[http://dx.doi.org/10.1016/j.ejps.2005.06.005] [PMID: 16087324]
[28]
Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today 2007; 12(23-24): 1068-75.
[http://dx.doi.org/10.1016/j.drudis.2007.09.005] [PMID: 18061887]
[http://dx.doi.org/10.1016/j.drudis.2007.09.005] [PMID: 18061887]
[29]
Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility. Pharm Res 2004; 21(9): 1598-606.
[http://dx.doi.org/10.1023/B:PHAM.0000041454.76342.0e] [PMID: 15497685]
[http://dx.doi.org/10.1023/B:PHAM.0000041454.76342.0e] [PMID: 15497685]
[30]
Johari GP, Kim S, Shanker RM. Dielectric studies of molecular motions in amorphous solid and ultraviscous acetaminophen. J Pharm Sci 2005; 94(10): 2207-23.
[http://dx.doi.org/10.1002/jps.20455] [PMID: 16136559]
[http://dx.doi.org/10.1002/jps.20455] [PMID: 16136559]
[31]
Wang X, Michoel A, Van den Mooter G. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. Int J Pharm 2005; 303(1-2): 54-61.
[http://dx.doi.org/10.1016/j.ijpharm.2005.07.002] [PMID: 16105723]
[http://dx.doi.org/10.1016/j.ijpharm.2005.07.002] [PMID: 16105723]
[32]
Gorman E, Mogalian E, Oliyai R, Stefanidis D, Zia V. Solid dispersion formulation of an antiviral compound. US2015064252, 2015.
[33]
Yunxia B, Rahman MA, Lester JD. Solid dispersion of poorly soluble compounds comprising cros povidone and at least one water-soluble polymer. US20150011525 2015.
[39]
Stefinoric M, Reece H. Solid dispersion comprising of µ- opioid
antagonists. US20180153879,. 2017.
[40]
Guo S, Gan Y, Zhang A, Miao Z, Gao L, Ding J. Somcl-9112 solid
dispersion and preparation method thereof and somcl-9112 solid preparation containing somcl-9112 solid dispersion. US20180133215,. 2018.
[41]
Temtem M, Pereir R, Duarte I. A method of preparing SD in submicron range by coprecipitation method. US20170209372, . 2017.
[43]
Sing WZ, Chen YW, Gang ZH. Methodsof preparing azilsartan by supercritical antIsolvent methods. CN108096195A. 2018.
[46]
Farah N, Bambarkar S. Pharmaceutical Composition Comprising Solid
Dispersion of BCS Class II Drugs with Gelucires. US20170119671,. 2017.
[47]
Bi Y, Rahman MA, Lester JD. Solid dispersion of poorly soluble
compounds comprising crospovidone and at least one water-soluble
polymer. US20150011525, . 2015.
[48]
Sun N, Zhang X, Lu Y, Wu W. In vitro evaluation and pharmacokinetics in dogs of solid dispersion pellets containing Silybum marianum extract prepared by fluid-bed coating. Planta Med 2008; 74(2): 126-32.
[http://dx.doi.org/10.1055/s-2008-1034294] [PMID: 18240100]
[http://dx.doi.org/10.1055/s-2008-1034294] [PMID: 18240100]
[49]
Shah B, Kakumanu VK, Bansal AK. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci 2006; 95(8): 1641-65.
[http://dx.doi.org/10.1002/jps.20644] [PMID: 16802362]
[http://dx.doi.org/10.1002/jps.20644] [PMID: 16802362]
[50]
Berndl G, Degenhardt M, Maegerlein M, Dispersyn G. Itraconazole
Compositions with Improved Bioavailability. US2009214656A1,. 2009.
[51]
Goyani SM, Shah P, Vyas B, Shah DR. A review on: Solid Dispersion for improvement of solubility in pharmaceutical dosage form. Int J Pharm Res Dev 2011; 4(2): 77-87.
[52]
Miyazaki T, Aso Y, Yoshioka S, Kawanishi T. Differences in crystallization rate of nitrendipine enantiomers in amorphous solid dispersions with HPMC and HPMCP. Int J Pharm 2011; 407(1-2): 111-8.
[http://dx.doi.org/10.1016/j.ijpharm.2011.01.035] [PMID: 21277962]
[http://dx.doi.org/10.1016/j.ijpharm.2011.01.035] [PMID: 21277962]
[53]
Luhadiya A, Agrawal S, Jain P, Dubey PK. A Review on Solid Dispersion. Int J Adv Res Pharm Bio Sci 2012; 1(2): 281-91.
[54]
Shamsuddin FazilM, Ansari SH, Ali J. Development and evaluation of SD of spironolactone using fusion method. Int J Pharm Invest 2016; 6(1): 63-8.
[55]
Aggarwal S, Gupta GD, Chaudhary S. SD as an eminent strategic approach in solubility enhancement of poorly soluble drugs. Int J Pharm Sci Res 2010; 1(8): 1-14.
[56]
Alvesa TF, Barrosa CT, Baldoa D, et al. Preparation, Characterization and ex vivo Intestinal Permeability Studies of Ibuprofen SD. J Disp Sci Tech 2018; 4(12): 22-33.
[58]
Zuo YJ, Hou W, Yanhua YL, Zhifang L. Bufotalin SD and preparation
method thereof. CN108175751A,. 2018.
[59]
Ya LX, Liu ZQ, Li CW, Chang Z, Pei JL, Hefei H. Curcubitacin B
solid dispesion and pepration method thereof. CN108042496A. 2018.
[61]
Michel WH. Polyvinylpyrolidine for the stablisation of SD of noncrystalline form of Rotrigotine. US20180147154,. 2018.
[64]
Shi S, Wang J, Yang KE, Yang T. Cilnidipine SD tablets & preparation method thereof. CN108210472A, 2017.
[65]
Xu Y, Tian N, Huang X, You J, Huang F. Lurasidone SD and preparation method thereof. WO2018127088A1, 2018.
[67]
Kyung HH. Pharmaceutical composition of sustained-release SD of
pelubiprofen and method for producing the same. KR101856911B1,
2017.
[70]
Umehera M, Uda A, Yamada Y. Method of producing solid dispersion
containing hardly soluble polyphenol. US20170273999, 2017.
[71]
Wang H, Fan Y, Chen X. Solid dispersion of decoquinate, a preparation process and its application. US10265270B2 2019.
[72]
Sheth A. Pavithra, Sundarajan, Miller, E. SD formulation of antiviral
compounds. US20170368031, 2017..
[73]
Cao R, Chen G, Fan Z, et al. SD containing desmodium stracifolium
merr. flavanoids, methods of preparing the same, & use thereof.
US20170028007, 2017.
[74]
Srinivasan S, Im HT, Yoon YS, et al. Amorphous SD compisingtaxane, tablet comprising the same and method for producing the same.
WO2015152544A1, 2015.
[75]
Battung F, Yvesjuvin P. Solid dispersion of a selective modulator of
the progesterone receptor. US20160213684, 2016..
[76]
Quetti M. SD of a pigment in the granules form and the relative preparation process. US20160017164, 2016.
[77]
Wang Y, Xiong Z, Zhang S, et al. Solid dispersion of tadalafil and
pharmaceutical excipients and preparation method of solid dispersion.
WO2017041679A1, 2017.
[78]
Nak AB, Hong MM, Hyeong PJ. , -min A Solid dispersion containing
dutasteride and composition containing the solid dispersion.
KR101561406B1, 2015..
[79]
Deshpande T, Ramesh G, Deshmukh K. Medicated chewing gum- an emerging intra-oral dosage form. Am J Pharmtech Res 2013; 3(2): 2249-3387.
[80]
Solid dispersion. http://www.solubest.com/media/Papers/SoluBest-DrugDelivery Tech20090708.pdf [23-5-2019];
[81]
The Coming of Age of Amorphous Solid Dispersions; https://www. pharmasalmanac.com/articles/the-coming-of-age-of-amorphous-solid-dispersions [accessed on 23-5-2019]..
[82]
Formulation development – KinetiSol; A New Processing Paradigm for Amorphous Solid Dispersion Systems https://www.businesswire. com/news/home/20130627006119/en/Formulation-Design-Platform-Poorly-Soluble-Compounds [accessed on 23-5-2019]..
[83]
Melt Extrusion Modeling and Formulation Information System (MemFis®). https://healthcare.evonik.com/sites/lists/nc/documentshc/evonik-brochure-memfis-en.pdf [accessed on 23-5-2019]
[84]
Heo MY, Piao ZZ, Kim TW, et al. Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole. Arch Pharm Res 2005; 28(5): 604-11.
[http://dx.doi.org/10.1007/BF02977766] [PMID: 15974450]
[http://dx.doi.org/10.1007/BF02977766] [PMID: 15974450]
[85]
Tran PHL, Tran TTD, Piao ZZ, et al. Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled discharge matrix tablet containing self-emulsifying SD. Int J Pharm 2013; 2(4): 22-33.
[86]
Tran PH, Tran TTD, Lee SA, et al. Roles of MgO release from polyethylene glycol 6000-based solid dispersions on microenvironmental pH, enhanced dissolution and reduced gastrointestinal damage of telmisartan. Arch Pharm Res 2011; 34(5): 747-55.
[http://dx.doi.org/10.1007/s12272-011-0508-2] [PMID: 21656360]
[http://dx.doi.org/10.1007/s12272-011-0508-2] [PMID: 21656360]
[87]
One contact, many experts. Solubility enhancement is our business.. https://healthcare.evonik.com/product/health-care/downloads/evonik-solubility-enhancement-brochure.pdf [accessed on 23-5-2019].
Related Books
Nanoparticles and Nanocarriers Based Pharmaceutical Formulations
Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part I
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part II
Mixed Polymeric Micelles for Osteosarcoma Therapy: Development and Characterization
A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems
Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part II)
Nanomaterials: Evolution and Advancement Towards Therapeutic Drug Delivery (Part I)
Article Metrics
72