Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates

Introduction: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs. Areas covered: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize™, closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug–carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, SolumerTM used to prepare stable amorphous SD. Expert opinion: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.

[1]  P. Dangprasirt,et al.  Development of diclofenac sodium controlled release solid dispersion powders and capsules by freeze drying technique using ethylcellulose and chitosan as carriers. , 1998, Drug development and industrial pharmacy.

[2]  Ahmed S. Ali,et al.  Preparation and Evaluation of Glipizide Tablets Containing both Enhanced and Sustained Release Solid Dispersions , 2010 .

[3]  S. Onoue,et al.  In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[4]  M. Rathbone,et al.  Amorphous Solid Dispersions , 2014, Advances in Delivery Science and Technology.

[5]  H. Cai,et al.  Preparation and in vivo ocular absorption studies of disulfiram solid dispersion. , 2000, Biological & pharmaceutical bulletin.

[6]  Mariarosa Moneghini,et al.  Characterization of solid dispersions of itraconazole and vitamin E TPGS prepared by microwave technology. , 2010, Future medicinal chemistry.

[7]  P. Tran,et al.  Investigation of physicochemical factors affecting the stability of a pH-modulated solid dispersion and a tablet during storage. , 2011, International journal of pharmaceutics.

[8]  G. Betageri,et al.  Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques , 1995 .

[9]  Lynne S Taylor,et al.  Evaluation of amorphous solid dispersion properties using thermal analysis techniques. , 2012, Advanced drug delivery reviews.

[10]  S. Torrado-Santiago,et al.  Changed crystallinity of mebendazole solid dispersion: improved anthelmintic activity. , 2011, International journal of pharmaceutics.

[11]  Mm Patel,et al.  Fast dissolving Valdecoxib tablets containing solid dispersion of Valdecoxib , 2006 .

[12]  H. Okada,et al.  Controlled release of drug via methylcellulose-carboxyvinylpolymer interpolymer complex solid dispersion , 2005, AAPS PharmSciTech.

[13]  H. Chen,et al.  Stabilization and sustained-release effect of misoprostol with methacrylate copolymer. , 2000, International journal of pharmaceutics.

[14]  J. Rantanen,et al.  Influence of solvent evaporation rate and formulation factors on solid dispersion physical stability. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[15]  Dave A. Miller,et al.  Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing , 2010, AAPS PharmSciTech.

[16]  K. Danjo,et al.  Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers. , 2004, Chemical & pharmaceutical bulletin.

[17]  Han‐Gon Choi,et al.  Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug. , 2011, International journal of pharmaceutics.

[18]  C. Roberts,et al.  Nanoscale thermal analysis of pharmaceutical solid dispersions. , 2009, International journal of pharmaceutics.

[19]  Manik,et al.  Formulation of Sustained-Release Dosage Form of Verapamil Hydrochloride by Solid Dispersion Technique Using Eudragit RLPO or Kollidon®SR , 2009, AAPS PharmSciTech.

[20]  R. Bogner,et al.  Formation of physically stable amorphous drugs by milling with Neusilin. , 2003, Journal of pharmaceutical sciences.

[21]  Y. Kawashima,et al.  Tabletting of solid dispersion particles consisting of indomethacin and porous silica particles. , 2005, Chemical & pharmaceutical bulletin.

[22]  R. Ibuki,et al.  Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II): in vivo evaluation. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[23]  C. Salomon,et al.  Development of prednisone: Polyethylene glycol 6000 fast-release tablets from solid dispersions: Solid-state characterization, dissolution behavior, and formulation parameters , 2007, AAPS PharmSciTech.

[24]  Claus-Michael Lehr,et al.  Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo. , 2012, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[25]  P. Tran,et al.  Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility , 2010, Expert opinion on drug delivery.

[26]  H. Sunada,et al.  Improvement of the dissolution rate of nitrendipine using a new pulse combustion drying method. , 2007, Chemical & pharmaceutical bulletin.

[27]  Lei Li,et al.  Characterization of Poly(Ethylene Oxide) as a Drug Carrier in Hot-Melt Extrusion , 2006, Drug development and industrial pharmacy.

[28]  Keith P. Johnston,et al.  Improvement of Dissolution Rates of Poorly Water Soluble APIs Using Novel Spray Freezing into Liquid Technology , 2002, Pharmaceutical Research.

[29]  C Vervaet,et al.  Development and evaluation of injection-molded sustained-release tablets containing ethylcellulose and polyethylene oxide , 2011, Drug development and industrial pharmacy.

[30]  Jochem Alsenz,et al.  Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions , 2010, Pharmaceutical Research.

[31]  P. Tran,et al.  The roles of acidifiers in solid dispersions and physical mixtures. , 2010, International journal of pharmaceutics.

[32]  Karthik Nagapudi,et al.  Manufacture and performance evaluation of a stable amorphous complex of an acidic drug molecule and Neusilin. , 2011, Journal of pharmaceutical sciences.

[33]  S. Schwendeman,et al.  Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(DL-lactide-co-glycolide) implants. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[34]  S. Gattani,et al.  Solubility Enhancement of Lovastatin by Modified Locust Bean Gum Using Solid Dispersion Techniques , 2008, AAPS PharmSciTech.

[35]  Geert Verreck,et al.  Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. , 2004, Journal of pharmaceutical sciences.

[36]  K. Mahadik,et al.  Study on mechanism for amorphous drug stabilization using gelucire 50/13. , 2009, Chemical and pharmaceutical bulletin.

[37]  R. Rajkó,et al.  Preparation of a solid dispersion by a dropping method to improve the rate of dissolution of meloxicam. , 2008, Drug development and industrial pharmacy.

[38]  Avinash Tekade,et al.  Microwave induced solubility enhancement of poorly water soluble atorvastatin calcium , 2010, The Journal of pharmacy and pharmacology.

[39]  S. Neau,et al.  The use of spray-drying to enhance celecoxib solubility , 2011, Drug development and industrial pharmacy.

[40]  S. Surana,et al.  Solubility, dissolution rate and bioavailability enhancement of irbesartan by solid dispersion technique. , 2011, Chemical & pharmaceutical bulletin.

[41]  R. Tan,et al.  Physical state and dissolution of ibuprofen formulated by co-spray drying with mesoporous silica: effect of pore and particle size. , 2011, International journal of pharmaceutics.

[42]  A. Millqvist-Fureby,et al.  Surface composition and contact angle relationships for differently prepared solid dispersions. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[43]  A. Nokhodchi,et al.  To enhance dissolution rate of poorly water-soluble drugs: glucosamine hydrochloride as a potential carrier in solid dispersion formulations. , 2010, Colloids and surfaces. B, Biointerfaces.

[44]  Géza Horváth,et al.  Comparison of solid dispersions produced by supercritical antisolvent and spray-freezing technologies. , 2009, International journal of pharmaceutics.

[45]  Indrajit Ghosh,et al.  Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder. , 2011, International journal of pharmaceutics.

[46]  A. C. Eissens,et al.  CLSM as Quantitative Method to Determine the Size of Drug Crystals in a Solid Dispersion , 2011, Pharmaceutical Research.

[47]  J. Schellens,et al.  Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). , 2011, International journal of pharmaceutics.

[48]  Dimitrios N Bikiaris,et al.  Solid dispersions, Part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs , 2011, Expert opinion on drug delivery.

[49]  Mariarosa Moneghini,et al.  Influence of the microwave technology on the physical-chemical properties of solid dispersion with Nimesulide , 2009 .

[50]  H. Tong,et al.  Comparison of Spray Freeze Drying and the Solvent Evaporation Method for Preparing Solid Dispersions of Baicalein with Pluronic F68 to Improve Dissolution and Oral Bioavailability , 2011, AAPS PharmSciTech.

[51]  A. C. Nunes,et al.  Effect of n-scCO(2) on crystalline to amorphous conversion of carbamazepine. , 2007, International journal of pharmaceutics.

[52]  Hoo-Kyun Choi,et al.  Preparation of a solid dispersion of felodipine using a solvent wetting method. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[53]  S. Bari,et al.  Preparation, characterization and in vivo evaluation of antihyperglycemic activity of microwave generated repaglinide solid dispersion. , 2012, Chemical & pharmaceutical bulletin.

[54]  P. Mahzouni,et al.  Colon Delivery of Budesonide Using Solid Dispersion in Dextran for the Treatment and Secondary Prevention of Ulcerative Colitis in Rat , 2010, International journal of preventive medicine.

[55]  K. Johnston,et al.  Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing. , 2007, International journal of pharmaceutics.

[56]  L. S. Taylor,et al.  A comparison of alternative polymer excipients and processing methods for making solid dispersions of a poorly water soluble drug. , 2001, International journal of pharmaceutics.

[57]  K. Johnston,et al.  Effect of Stabilizer on the Maximum Degree and Extent of Supersaturation and Oral Absorption of Tacrolimus Made By Ultra-Rapid Freezing , 2007, Pharmaceutical Research.

[58]  H. Wikström,et al.  Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture , 2011, AAPS PharmSciTech.

[59]  M. Sankalia,et al.  Effect of hydrophilic swellable polymers on dissolution enhancement of carbamazepine solid dispersions studied using response surface methodology , 2007, AAPS PharmSciTech.

[60]  Lisa J. Graham,et al.  A Model-Based Methodology for Spray-Drying Process Development , 2009, Journal of Pharmaceutical Innovation.

[61]  Y. Khimyak,et al.  Amorphous drug-PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state. , 2009, Journal of pharmaceutical sciences.

[62]  Xing Tang,et al.  Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion , 2007, Drug development and industrial pharmacy.

[63]  M. El-Badry Physicochemical Characterization and Dissolution Properties of Meloxicam-Gelucire 50/13 Binary Systems , 2011, Scientia pharmaceutica.

[64]  A. Madgulkar,et al.  Studies on Formulation Development of Mucoadhesive Sustained Release Itraconazole Tablet Using Response Surface Methodology , 2008, AAPS PharmSciTech.

[65]  M. Fujii,et al.  Effect of particle size of drug on conversion of crystals to an amorphous state in a solid dispersion with crospovidone. , 2011, Chemical & pharmaceutical bulletin.

[66]  A. E. Del Río Castillo,et al.  Applications of supercritical fluids to enhance the dissolution behaviors of Furosemide by generation of microparticles and solid dispersions. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[67]  H. Okamoto,et al.  Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique. , 2004, Chemical & pharmaceutical bulletin.

[68]  Dimitrios N Bikiaris,et al.  Solid dispersions, Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs , 2011, Expert opinion on drug delivery.

[69]  Simon Bates,et al.  Evaluation of Drug-Polymer Miscibility in Amorphous Solid Dispersion Systems , 2009, Pharmaceutical Research.

[70]  Sullivan Mf,et al.  Sustained release of naltrexone from glyceride implants. , 1976 .

[71]  R. Mashru,et al.  A Novel Itraconazole Bioadhesive Film for Vaginal Delivery: Design, Optimization, and Physicodynamic Characterization , 2009, AAPS PharmSciTech.

[72]  J. Parikh,et al.  Preparation and Characterization of Co-Grinded Mixtures of Aceclofenac and Neusilin US2 for Dissolution Enhancement of Aceclofenac , 2009, AAPS PharmSciTech.

[73]  Yanfei Luo,et al.  Evaluation of polymer carriers with regard to the bioavailability enhancement of bifendate solid dispersions prepared by hot-melt extrusion , 2012, Drug development and industrial pharmacy.

[74]  Ying Li,et al.  Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers. , 2011, International journal of pharmaceutics.

[75]  D. Bikiaris,et al.  Improvement in chemical and physical stability of fluvastatin drug through hydrogen bonding interactions with different polymer matrices. , 2009, Current drug delivery.

[76]  G. Tejal,et al.  Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution , 2010, Acta pharmaceutica.

[77]  Y. Kawashima,et al.  Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[78]  R. Bodmeier,et al.  Characterization and stability of solid dispersions based on PEG/polymer blends. , 2010, International journal of pharmaceutics.

[79]  Andrea Hanefeld,et al.  Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion. , 2011, Journal of pharmaceutical sciences.

[80]  Sumie Yoshioka,et al.  Miscibility of nifedipine and hydrophilic polymers as measured by (1)H-NMR spin-lattice relaxation. , 2007, Chemical & pharmaceutical bulletin.

[81]  Sunil K. Jain,et al.  Development and in vitro evaluation of ibuprofen mouth dissolving tablets using solid dispersion technique. , 2010, Chemical & pharmaceutical bulletin.

[82]  Raimar Löbenberg,et al.  Physicochemical Characterization of Solid Dispersions of Indomethacin with PEG 6000, Myrj 52, Lactose, Sorbitol, Dextrin, and Eudragit® E100 , 2004, Drug development and industrial pharmacy.

[83]  Jing Li,et al.  Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent. , 2009, Journal of pharmaceutical sciences.

[84]  R. Bogner,et al.  Effect of the pH grade of silicates on chemical stability of coground amorphous quinapril hydrochloride and its stabilization using pH-modifiers. , 2009, Journal of pharmaceutical sciences.

[85]  T. Ozeki,et al.  Controlled release from solid dispersion composed of poly(ethylene oxide)-Carbopol interpolymer complex with various cross-linking degrees of Carbopol. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[86]  S. Shanmugam,et al.  Preparation and evaluation of Cremophor‐free paclitaxel solid dispersion by a supercritical antisolvent process , 2011, The Journal of pharmacy and pharmacology.

[87]  S. Okonogi,et al.  Dissolution improvement of high drug-loaded solid dispersion , 2006, AAPS PharmSciTech.

[88]  Tomio Nakano,et al.  The role of the kneading paddle and the effects of screw revolution speed and water content on the preparation of solid dispersions using a twin-screw extruder. , 2002, International journal of pharmaceutics.

[89]  H. Okamoto,et al.  Preparation of functional composite particles of salbutamol sulfate using a 4-fluid nozzle spray-drying technique. , 2008, Chemical & pharmaceutical bulletin.

[90]  Lawrence X. Yu,et al.  Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis. , 2012, International journal of pharmaceutics.

[91]  G. Van den Mooter,et al.  Review: physical chemistry of solid dispersions. , 2009, The Journal of pharmacy and pharmacology.

[92]  Ashok R. Patel,et al.  Evaluation of SLS: APG Mixed Surfactant Systems as Carrier for Solid Dispersion , 2008, AAPS PharmSciTech.

[93]  F. Vrečer,et al.  Solid dispersions of carvedilol with porous silica. , 2011, Chemical & pharmaceutical bulletin.

[94]  Michael P Sigalas,et al.  Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[95]  M. Maghsoodi,et al.  Preparation and evaluation of solid dispersions of piroxicam and Eudragit S100 by spherical crystallization technique , 2010, Drug development and industrial pharmacy.

[96]  W. Hinrichs,et al.  Characterization of a cyclosporine solid dispersion for inhalation , 2007, The AAPS Journal.

[97]  Dave A. Miller,et al.  Applications of KinetiSol dispersing for the production of plasticizer free amorphous solid dispersions. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[98]  M. Harris,et al.  Evaluation of the microstructure of semicrystalline solid dispersions. , 2010, Molecular pharmaceutics.

[99]  Lieven Baert,et al.  Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion--Part I. , 2003, International journal of pharmaceutics.

[100]  K. Johnston,et al.  Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process , 2007, AAPS PharmSciTech.

[101]  Keith P. Johnston,et al.  Enhanced Aqueous Dissolution of a Poorly Water Soluble Drug by Novel Particle Engineering Technology: Spray-Freezing into Liquid with Atmospheric Freeze-Drying , 2003, Pharmaceutical Research.

[102]  P. Maincent,et al.  Crystallinity and dissolution rate of tolbutamide solid dispersions prepared by the melt method. , 1984, Journal of pharmaceutical sciences.

[103]  N. Barakat,et al.  Etodolac-Liquid-Filled Dispersion into Hard Gelatin Capsules: An Approach to Improve Dissolution and Stability of Etodolac Formulation , 2006, Drug development and industrial pharmacy.

[104]  A. Hussein,et al.  Kneading Technique for Preparation of Binary Solid Dispersion of Meloxicam with Poloxamer 188 , 2009, AAPS PharmSciTech.

[105]  S. Brocchini,et al.  Anomalous properties of spray dried solid dispersions. , 2009, Journal of pharmaceutical sciences.

[106]  B. Perissutti,et al.  Processing of carbamazepine-PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterisation, and in vitro dissolution. , 2001, International journal of pharmaceutics.

[107]  F. Princivalle,et al.  Microwave generated solid dispersions containing Ibuprofen. , 2008, International journal of pharmaceutics.

[108]  K. Danjo,et al.  An Attempt to Stabilize Nilvadipine Solid Dispersion by the Use of Ternary Systems , 2003, Drug development and industrial pharmacy.

[109]  Qi Chang,et al.  Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound. , 2011, International journal of pharmaceutics.

[110]  F. Sale,et al.  Some factors influencing dissolution from salicylic acid‐urea solid dispersions , 1976, The Journal of pharmacy and pharmacology.

[111]  Vesa-Pekka Lehto,et al.  Predicting the formation and stability of amorphous small molecule binary mixtures from computationally determined Flory-Huggins interaction parameter and phase diagram. , 2010, Molecular pharmaceutics.

[112]  H. Sunada,et al.  Preparation and evaluation of Ibuprofen solid dispersion systems with kollidon particles using a pulse combustion dryer system. , 2007, Chemical & pharmaceutical bulletin.

[113]  A. C. Eissens,et al.  Solid dispersions based on inulin for the stabilisation and formulation of delta 9-tetrahydrocannabinol. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[114]  Deepak Bahl,et al.  Amorphization of Indomethacin by Co-Grinding with Neusilin US2: Amorphization Kinetics, Physical Stability and Mechanism , 2006, Pharmaceutical Research.