The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have been employed to enhance the dissolution rates of poorly water – soluble drugs. This article reports various solubility enhancement strategies in solid dispersion. The approaches described are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology. The paper also highlights the potential applications and limitations of these approaches in solid dispersions.
Keywords: micronization, lyophilization, melt agglomeration, extruding, amorphous state, bioavailability, solubility, dissolution
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The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all the drug substances and pharmaceutical ingredients to be used in fabricating the product. An important physical-chemical property of a drug substance is solubility, especially aqueous system solubility. Solubility is a predetermined and rate limiting step for absorption. Drugs must have to enter in to the systemic circulation to exert a therapeutic effect1. In recent technologies, innovation of combinatorial chemistry and high throughput screening can effectively discover the seeds of new drugs which exhibit good pharmacological activities however 35-40 % of these new drugs discovered by those technologies suffer from poor aqueous solubility2-3. Consideration of the modifed Noyes-Whitney equation 4, 5 provide some hints regarding how the dissolution rate of very poorly soluble compounds improved to minimize the limitations to oral bioavailability:
dC /dt = AD(Cs â€“ C) / h
where dC/dt is the rate of dissolution, A is the surface are available for dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of the compound in the dissolution medium, C is the concentration of drug in the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound. To increase the dissolution rate from equation the following approaches are available.
a) To increases the surface area available for dissolution by:
b)Decreasing the particle size of drug.
c)Optimizing the wetting characteristics of compound surface.
d)To decrease the boundary layer thickness
e)Ensure sink condition for dissolution
f)Improve apparent solubility of drug under physiologically relevant conditions. Drug administered in fed state is a way to improve the dissolution rate6.Â The solubility/dissolution behavior of a drug is key determinant to its oral bioavailability, the latest frequency being the rate-limiting step to absorption of drugs from the gastrointestinal tract7-8. Consequently poor solubility results in low bioavailability, increase in the dosage, large inters and intra-subject variation and large variations in blood drug concentrations under fed versus fasted conditions. Improvement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. The techniques/ approaches that have commonly been used to overcome drawbacks associated with poorly water-soluble drugs, in general includes micronization, salt formation, use of surfactant and use of pro- drug 7-8 however all these techniques have certain limitations. Â Micronization has several disadvantages, the main one being the limited opportunity to control important characters of the final particle such as size, shape, morphology, surface properties and electrostatic charges. In addition micronization is a high-energy process, which causes disruptions in the drug s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product. The amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions9, 10, 11 . All poorly water-soluble drugs are not suitable for improving their solubility by salt formation. The dissolution rate of a particular salt is usually different form that of parent compound. However sodium and potassium salts of weak acids dissolve more rapidly than the free salts. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug, epigastric distress due to high alkalinity. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Even though particle size reduction increases the dissolution rate, the formed fine powders showing poor wettability and flow properties. Solid dispersion technique has come into existence to eliminate all these problems 12-13. Solid dispersion (SD) technique has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water-soluble drugs14-15. In solid dispersion the drugs are dispersed in a biologically inert matrix for the intention of enhancing oral bioavailability. Chiou and Riegelman defined these systems as the dispersion of one or more active ingredient in an inert carrier matrix at solid state prepared by the melting (fusion), solvent or melting-solvent method.16 However, the most attractive option for increasing the release rate is improvement of the solubility through formulation approaches.
Table 1 summarizes the various approaches that can be taken to improve the solubility or to increase the available surface area for dissolution. Review articles have already been published on the use of polymorphs 17, the amorphous form of the drug 18 and complexation 19, 20.
Solubility enhancement strategies in solid dispersions:
Various strategies investigated by several investigators include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology.
The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. This process employs melting of the mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after fusion, the sample are poured onto a metallic plate which is kept at ice bath. A modification of the process involves
Spray congealing from a modified spray drier onto cold metal surface. Decomposition should be avoided and is affected by fusion time and rate of cooling21-22. Another modification of the above method, wherein SD(s) of troglitazone- polyvinyl pyrrolidone (PVP) k 30 have been prepared by closed melting point method. This method involves controlled mixing of water content to physical mixtures of troglitazone PVP k30 by storing at various equilibrium relative humidity levels (adsorption method) or by adding water directly (charging method) and then mixer is heated. This method is reported to produce SD with 0% apparent crystallinity23. On the other hand, the fusion process does not require an organic solvent but since the melting of sparingly water-soluble drug and water-soluble polymer entails a cooling step and solid pulverizing step, a time consuming multiple stage operation is required. To overcome this problem Nakano et al 24 have described a method conceptualizing the formation of a SD as the solid-to-solid interaction between a sparingly water soluble drug, nilvadipine and water soluble polymer which, unlike conventional production method, comprises mixing a sparingly water soluble drug and water soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, instead of heating the system to the extent that the two materials are melted , the sparingly water soluble drug can be made amorphous to have never been achieved by any dry process heretofore known.
Solvent evaporation method:
The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. Large volumes of solvents are generally required which can give rise to toxicological problems 25-26. Many investigators studied SD of meloxicam, naproxen27-28, rofecoxib29, felodipine30, atenolol 31, and nimesulide32 using solvent evaporation technique. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs. Suhagic et al. 33 prepared SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected. The prepared SD(s) exhibited improved dissolution attributed to decreased crystallinity, improved wetting and improved bioavailability.
Freeze-drying involves transfer of heat and mass to and from the product under preparation34. Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Betageri et al. 35, Topalogh et al. 36, Badry et al. 37 and Fathy et al.38 have successfully investigated the potential applications of lyophilization in manufacturing of SD(s). Drooge et al39 suggested spray freeze-drying as a potential alternative to the above-mentioned process to produces 9- tetrahydrocannabino containing inulinbased solid dispersions with improved incorporation of – tetrahydrocannabino in inulin.
Melt agglomeration process:
This technique has been used to prepare SD where the binder acts as a carrier. Binder (carrier), drug and excipients are heated to temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer40. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates41. Larger particles results in densification of agglomerates while fine particle cause complete adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles41-43.
The extruding method was originally designed as an extraction / casting method for polymer alloys in plastic industry, is now used to process cereals and functionalize food materials, such as tissue products from animal proteins44. Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant45. The extruder consists of a hooper, barrel, a die, a kneading screw and heaters. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die44. The effect of screw revolution speed and water content on the preparation of SD(s) should be investigated, since these parameters have profound impact on the quality of SD(s). Nakamichi et al 46, studied that presence of kneading paddle element of screw results in super saturation on dissolution testing while slow revolution rate of screw and addition of the suitable amount of water increased rate of dissolution although no super saturation occurred. In addition, high screw speed high feed rate processes in comparison with low screw speed low feed rate processes caused an increase in extrudate radius and porosity and decrease in mechanical strength and drug release rate from the matrix attributed to the expansion promoted under certain extrusion conditions47. To reduce the melt viscosity in the extrudate and to be able to decrease temperature settings, a plasticizer can be added to the formulation. Typically, conventional plasticizer such as triacetin or polyethylene glycol is used in concentration range of 5-30 % weight of the extrudate that lowers the processing temperature. Carbon dioxide can act as temporary plasticizer. During extrusion carbon dioxide is transformed in gaseous phase. As a consequence carbon dioxide escapes from extrudate and does not appear in final product48. The role of methylparaben49 and sorbitol50 has also been investigated as plasticizer in preparation of SD(s) in extrusion method. This method has already been used successfully to prepare SD(s) of i traconazole and hydroxypropylmethylecellulose (HPMC) 51, indomethacin/lacidipine/nefidipine/ piroxicam/ tobutamide and polyvinylpyrrolidone (PVP) 52, itraconazole53 and HPMC 2910/ Eudragit e 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution rate of poor water soluble drugs.
The manufacture of milk powder was one of the first applications of spray drying when the method was developed in 1920. Today, spray drying finds great utility in pharmaceutical industry because of the rapid drying and specific characteristics such as particle size and shape of the final product. In addition, it is simple and cost effective, as it is 30-50 times less expensive than freeze-drying. It is an established method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process, resulting solid particles. The process allows production of fine, dust free powder as well as agglomerated one to precise specifications. The operating conditions and dryer design depends upon the drying characteristics of the product and require powder specifications 54-56. Rankell et al. prepared SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. After spray drying, the dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane. The prepared SD(s) exhibited higher dissolution rates than that of pure crystalline loperamide57. Chouhan et al 58 studied the suitability of this technique for preparation of SD(s) of glibenclamide polyglcolized glycerides. This study revealed the improvement in solubility and dissolution rates, also improvement in the therapeutics efficacy of amorphous glibenclamide in SD(s) was observed. Some other investigators 59-60 also reported improvement in solubility and dissolution rate. The frequent use of the organic solvent in spray drying pose problems such as residues in products, environmental pollution and operational safety as well as corporate problems such as capital investment. Tanno et al61described a process for producing the SD(s) of poorly water-soluble drugs using water-soluble polymer dispersion and/ or water-soluble polymer solution and the plasticizer solution by using 4-nozzle spray gun. The spray drying technique is a useful method to obtain spherical particle and narrow distribution. The role of porous materials such as calcium silicate, controlled pore glass and porous cellulose is appreciated to formulate solid dosages forms because they confer special characteristics such as decrease of melting point and a decrease in the crystallinity of drug entrapped in pores. In addition, porous materials control polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions. Moreover, porous silica has been reported to improve solubility and dissolution rates of indomethacin and tolbutamide 62-63.
The use of surfactant:
The utility of the surfactant systems in solubilization is well known. Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have attracted the attention of investigators for preparation of solid dispersions64- 65. Recently a new class of surfactant known as Gelucires are introduced which identify by melting points and HLB values. Gelucire is a widely use in the formulation of semi solid dispersions. Gelucire is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol (PEG) derived from natural vegetable fatty acids and having amphiphilic character. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release. Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point, while 14 and 313 represent HLB values of gelucire respectively 66-67. Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000- gelucire 44/14 and UC-781- PEG 6000-gelucire 44/14- PVP k 30 were studied. Improvement in solubility, dissolution and stability was observed 68-69. Labrasol, of same chemical nature as gelucire, is a clear liquid surfactant with a HLB of 14. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug 66-67. The amphiphilic poly (ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as poloxamer or pluronics represent another class of surfactants. These are available in various molecular weights and PEO/PPO ratios, and hence offer a large variety of physico-chemical properties 70. These block polymers are extensively used in the pharmaceutical industry as defoaming agents, gelling agents, detergents, dispersing agents, emulsifying agents and solubilizing agents71. When used in relatively high quantities, poloxamer imparts sustained-release properties to solid dosage forms, by forming a lipid matrix72. Solid dispersions using pluronic F-68 (a type of poloxamer) as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water- soluble compound. Results showed that the solid dispersion substantially increased the in vitro-dissolution rate of ABT-963. A significant increase of oral bioavailability compared with conventional capsule formulation was also reported73. The presence of water and polar water-miscible solvent, a partially water-miscible solvent, a non- ionic surfactant, an anionic surfactant and cationic surfactant affect domain of the PEO-PPO-PEO block copolymer selfassembly74. Therefore, organic solvents and surfactants should be used with great care for preparation solid dispersion while using in combination with poloxamer. Inutec SPI, a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone in the presence of a basic catalyst such as a tertiary amine or lewis acid, has also been evaluated as carrier in formulation of solid dispersions for a poorly water- soluble drug. Inutec SPI has low viscosity and stability effect on emulsion and suspension. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI4. Hemant et al 75 and Sheen et al 76 studied that polysorbate 80, a commonly used surfactant, results in improvement of dissolution and bioavailability of poorly watersoluble drug attributed to solubilization effect of surface active agent. Polysorbate 80 also ensues complete release of drug in metastable finely dispersed state having large surface area.
Super critical fluid (scf) technology:
This technology has been introduced in the late 1980s and early 1990s, and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. Since the first experiences of Hannay et al in 1879, a number of techniques have been developed and patented in the field of SCF-assisted particle design. These methods use. SCFs either as solvent: rapid expansion from supercritical solution (RESS) or anti-solvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance79. Solution enhanced dispersion by supercritical fluids (SEDS), aerosol solvent extraction system (ASES), supercritical anti-solvent (SAS), gas anti-solvent (GAS) and precipitation with a compressed fluid anti-solvent (PCA) are process of micronization. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing cocurrently80. The use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature81. Supercritical fluids used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component) 82. Wong et al compared the SD(s) of felodipine prepared by conventional solvent evaporation (CSE) and supercritical antisolvent precipitation (SAS) methods. The particle sizes of the SD(s) from CSE process increased at 1h after dispersed in distilled water. However the particle sizes of the SD(s) from SAS process were maintained for 6 h due to the increased solubility of felodipine. Moreover, SD(s) form the SAS process showed a high dissolution rate of over 90% within 2 h showing the potential applications of SCE technology in preparation of SD(s) 83.
Summary And Future Potential:
The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration resulting in low bioavailability. Solubility enhancement of these drugs remains one of the most challenging aspects of drug development. A variety of devices have been developed over the years to enhance the drug solubility and dissolution of the drugs. The solid dispersion method is one of the effective approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs. Various techniques, described in this review, are successfully used for the preparation of SD(s) in the bench and lab scale and can be used at industrial scale also. Solid dispersions came into limelight in pharmaceutical development due to the increasing number of drug candidates which are poorly soluble and the substantial improvements in the manufacturing methods for solid dispersions that have been made in the last few years. Although there are some hurdles like scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion technology will hasten the drug release profile of poorly water soluble drugs.
I am very much thankful to my research guide and co- guide, Dr.N.M.Patel and Dr.M.M.Patel respectively for their constant encouragement and help to write this review.
1. Ansel H C, Allen L V and Popovich CG. Eds. In; Pharmaceutical dosage forms and drugÂ delivery systems, 7th Edn, Lippincott Williams and Wilkins, 2000, 60-61,66.
2. Ohara T, Kitamura S, Kitagawa T and Terada K. Dissolution mechanism of poorly water- soluble drug from extended solid dispersion system with ethyl cellulose and hydroxypropyl
methylcellulose. Int. J. Pharm. 302, 2005, 95-102.
3. Mooter G V den, Weuts I, Rider T D and Blaton N. Evaluation of Inutec SPI as a new carrierÂ inÂ the formulation of solid dispersion for poorly water drugs. Int. J.Pharm. 316, 2006, 1-6.
4. A.A. Noyes, W.R. Whitney, The rate of solution of solid substances in their own solutions, J. Am. Chem. Soc. 19 (1897) 930-934.
5. W. Nernst, Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen, Zeitschrift f.Â Â Physik. Chemie 47 (1904) 52-55.
6. E. Galia, E. Nicolaides, D. HoÃˆrter, R. LoÃˆbenberg, C. Reppas, J.B. Dressman, EvaluationÂ of various dissolution media for predicting in vivo performance of class I and II drugs, Pharm.Â Â Res. 15 (1998) 698-705.
7.Patro S, Himasankar K, Choudhury A A and Rao M E B. Effect of some hydrophilicpolymers on dissolution rate of roxitromycin. Indian J. Pharm. Sci. 67(3), 2005, 334-341.
8.Omaima A S, Mohammed A H, Nagia A M and Ahmed S Z. Formulation and optimization of mouth dissolve tablets containing rofecoxib solid dispersions. AAPSÂ PharmSciTech 7(2), 2006, E1-E9.
9.Hecq J, Deleers M, Fanara D, Vranckx H and Amighi K. Preparation and characterization of nanaocrystals for solubility and dissolution rate enhancement of nifidipine. Int. J. Pharm. 299,Â Â 2005,167-177.
10.Takano, Niichiro, Kawashima, Hiroyuki, Shinoda, Yasuo, Inagi and Toshio. Solid dispersion compositions. United States Patent No. 6753330, 2004.
11.Yiyun C, Tongwen X and Rongqiang F. Polyamidoamine dendrimers used as solubility
enhances of ketoprofen. Eur. J. Med. Chem. 40, 2005, 1390-1393.
12.Mohan Babu G V M, Prasad D S, and Raman Murthy K V. Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug Nimodipine. Int. J. Pharm. 234, 2002, 1-17.
13.Gibaldi M. Ed., In; Biopharmaceutics and clinical pharmacokinetics, 4th Edn, Pharma Book Syndicate, Hyderabad, 2005, 48
14.Tanaka N, Imai K, Okimoto K, Ueda S, Rinta Ibuki Y T, Higaki K and Kimura T. Development of novel sustained-release system, disinmtegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilcadipine (II): In vivo evaluation. Journal of controlled release 122, 2006, 51- 56.
15.Duncan Q M C. The mechanism of drug release from solid dispersions in water-soluble polymers. Int. J. Pharm. 231, 2002, 131-144.
16.Hayes, Davis, Morella and Angelo Mario. Pharmaceutical compositions for poorly water-soluble drugs. United States Patent. No. 6881745,2005.
17.J.-O. Henck, U.J. Griesser, A. Burger, Polymorphie von Arzneistoffen, Pharm. Ind. 59 (1997) 165-169.
18.B.C. Hancock, G. Zografi, Characteristics and significance of the amorphous state in pharmaceutical systems (review), J. Pharm. Sci. 86 (1997) 1-12.
19. D. Hoerter, J.B. Dressman, Influence of physicochemical properties on dissolution of drugsÂ in the gastrointestinal tract (review), Adv. Drug Delivery Rev. 25 (1997) 3-14.
20. T.Loftsson, M.E. Brewster, Pharmaceutical application of cyclodextrins.Drug solubibilisation and stabilization (review), J.Pharm. Sci. 85 (1996) 1017-1025
21.Zerrouk N, Chemtob C, Arnaud P, Toscani S Â and Dugue J. In vitro and in vivo evaluation of carbemazepine-PEG 6000 solid dispersions. Int. J. Pharm. 225, 2001, 49-62.
22.Boral A, Sen N, Ghosh L K and Gupta B K. Solid Dispersion technology for controlling drug release and absorption. The eastern pharmacist, April 1995, 141-143.
23. Hasegawa S, Hamaura T, Furuyama N, Kusai A, Yonemochi E and Terada K. Effects ofÂ water contents in physical mixture and heating temperature on crystallinity of troglitazone- PVP K 30 solid dispersions prepared by closed melting method. Int. J. Pharm. 302, 2005, 103-112.
24. Nakano, Minoru, Uemura, Toshinobu, Morizane, Shinichi, Okuda, Kiyoshi, Nakata and Keiko. Method of producing a solid dispersion of a sparingly water-soluble drug, nilvadipine. United State Patent No. 5340591, 1994
25. Butler and Mattew J. Method of producing a solidÂ dispersion of a poorly water-soluble drug. United State Patent No. 5985326,1999.
26. Kim Eun-Jung, Chun M K, Jang J S, Lee I H, K R L and Choi H K. Preparation of a solidÂ Â dispersion of felodipine using a solvent wetting method.
27.Chowdary K P R and R. Hymavathi. Enhancement of dissolution rate of meloxicam. Indian J. Pharm. Sci. April 2001, 150-154.
28. Rao M G, Suneetha R, Reddy P S and Ravi T K. Preparation and evaluation of solid dispersions of naproxen. Indian J. Pharm. Sci. 67(1), 2005,26-29.
29.Mura P, Zerrouk N, Mennini N, Masterly F and Chemtob C. Development and characterization of naproxen solid systems with improved drug dissolution properties. Eur. J. Pharm. Sci. 18, 2003, 67-75.
30.Soniwala M M, Patel P R, Mansuri N S, Parikh R K and Gohel M C. Indian J. Pharm. Sci 67(1), 2005, 61-65.
31.Moneghini M, Carcano A, Zingone G and Perissutti. Studies in dissolution enhancement of atenolol. Int. J. Pharm. 175, 1998, 177-183.
32.Jain R K, Sharma D K, Jain S, Kumar S and Dua J S . Studies on solid dispersions ofÂ Â nimesulide with pregelatinized starch. Biosciences, biotechnology research Asia 3(1a), 2006, 151-153.
33.Suhagia B N, Patel H M, Shah S A, Rathod I and Parmar V K. Acta Pharm 56, 2006, 285-298.
34. Tsinontides S C, Rajniak P, Pham D, Hunke W Â A, Placek, J and Reynolds S D. Freeze drying- principles and practice for successful scale-up to manufacturing. Int. J. Pharm. 280,Â No. 1, 2004, Â Â Â Â Â 1-16.
35. Betageri G V and Makarla K R. Enhancement of dissolution of Glyburide by solid dispersion and lyophilization techniques. Int. J. Pharm. 126, 1995, 155-160.
36.Yalcin T, Gulgun Y and Gonullu U. Inclusion of ketoprofen with skimmed milk by freeze-drying. Il Farmaco 54, 1999, 648-652.
37.Bandry M B and Fathy M. Enhancement of the dissolution and permeation rates of meloxicam by formation of its freeze-dried solid dispersions in polyvinylpyrrolidone K-30. Drug Dev. Ind. Pharm. 32 (2), 2006 Feb, 141-150.
38.Fathy M and Sheha M. In vitro and in vivo evaluation of an amylobarbitone /hydroxypropyl-betacyclodextrin complex prepared by a freeze-drying method. Pharmazie. 55 (7), 2000 Jul, 513-517.
39.Â Drooge D J V, Hinrichs W L J, Dickhoff H J, Elli M N A, Visser M R, Zijlastra G S andÂ Â Frijlink H W. Spray freeze drying to produce a stable 9- tetrahydrocannabino containing inulin based solid dispersion powder suitable for inhalation. Eur. J. Pharm. 26, 2005, 231-240.
40. Seo A, Holm P, Kristensen H G, Schaefer T. The preparation of agglomerates containing solid dispersions of diazepam by melts agglomeration in a high shear mixer. Int. J. Pharm. 259(1-2), 2003 Jun 18, 161-71.
41.Vilhelmsen T, Eliasen H, Schaefer T. Effect of a melt agglomeration process on agglomerates containing solid dispersions. Int. J. Pharm. 303(1- 2), 2005 Oct 13, 132-142.
42.Vilhelmsen T, Schaefer T. Agglomerate formation and growth mechanisms during melt agglomeration in a rotary processor. Int. J. Pharm. 304 (1- 2), 2005 Nov 4, 152-164.
43. Seo A and Schaefer T. Melt agglomeration with polyethylene glycol beads at a low impeller speed in a high shear mixer. Eur. J. Pharm. Biopharm. 52(3), 2001 Nov, 315-325.
44.Wang L, Cui F D, Hayse T and Sunada H. Preparation and evaluation of solid dispersion for nitrendipine- carbopol and nitrendipine HPMCP systems using twin screw extruder. Chem. Pharm. Bull. 53(10), 2005, 1240-1245
45.Zajc N, Obreza A, Bele M and Srcic S. Physical properties and dissolution behavior ofÂ Â Â nefidipine/ mannitol solid dispersions prepared by hot melt method. Int. J. Pharm. 291, 2005, 51-58.
46.Nakamichi K, Nakano T, Yasuura H, Izumi S and Kawashima Y. The role of the kneadingÂ paddle and the effects of screw revolution speed and water content on the preparation of solid dispersions using a twin-screw extruder. Int. J. Pharm. 241(2), 2002 Jul 25, 203-211.
47. Six K, Verreck G, Peeters J, Brewster M and Van Den Mooter G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J. Pharm. Sci. 93(1), 2004 Jan, 124-131.
49.Verreck G, Decorte A, Heymans K, Adriaensen J, Liu D, Tomasko D, Arien A, Peeters J, Mooter G V den and Brewster M E. Hot stage extrusion of pamino salicylic acid with EC using CO2 as a temporary plasticizer. Int. J. Pharm. 327, 2006, 45 50.
50.Wu C and Mc Ginity J W. Influence of methylparaben as a solid-state plasticizer on theÂ physicochemical properties of Eudragit RS PO hot-melt extrudates. Eur. J. Pharm. Biopharm. 56(1), 2003 Jul, 95-100.
51.Â Zajc N, Obreza A, Bele M and Srcic S. Physical properties and dissolution behavior of nefidipine/ mannitol solid dispersions prepared by hot melt method. Int. J. Pharm. 291, 2005,51-58.
52. Six K, Berghmans H, Leuner C, Dressman J, Van Werde K, Mullens J, Benoist L, ThimonÂ M, Meublat L, Verreck G, Peeters J, Brewster M and Van den Mooter G. Characterization of solid dispersions of itraconazole and hydroxypropyl- methylcellulose prepared by melt extrusion, Part II. Pharm. Res. 20(7), 2003 Jul, 1047-1054.
53.Forster A, Hempenstall J, Tucker and Rades T. The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Dev. Ind. Pharm. 27(6), 2001 Jul, 549-560.
54. Six K, Daems T, de Hoon J, Van Hecken A, Depre M, Bouche MP, Prinsen P, Verreck G, Peeters J, Brewster ME and Van den Mooter G. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur. J. Pharm. Sci. 24(2-3), 2005 Feb, 179-186.
55.Chronakisa I S, Triantafyllou A O, R OÂ¨ ste. Solidstate characteristics and redispersible properties of powders formed by spray-drying and freeze-drying cereal dispersions of varying (1 3, 1 4)-ÃŸ -glucan content. Journal of cereal science 40, 2005, 183-193.
56.Patrice T T, Stephanie B and Hatem F. Preparation of redispersible dry nanocapsules by means of spray drying: Development and characterization. Eur. J. Pharm. Sci. 30, 2007, 124 135.
57. Rankell A S, Lieberman H A and Schiffmann R F. Drying. In: L. Lachman , H.A. Lieberman and J.L.Kanig eds. The theory and practice of industrial pharmacy. 3rd edition, Varghese Publishing house, Bombay, 1987, pp no 61.
58.Weuts I, Kempen D, Verreck G, Decorte A, Heymans K, Peeters J, Brewster M and Mooter G V den. Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG 6000 prepared by spray drying. Eur. J. Pharm. Biopharm. 59, 2005, 119-126. Gelucire 44/14 and Labrasol . Il Farmaco 60,2005,777-782.
59. Chauhan B, Shimpi S and Paradkar A. Preparation and evaluation of glibenclamidepolyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. Eur. J. Pharm. Sci. 26,2005, 219-230.
60. Ueno Y, Yonemochi E, Tozuka Y, Yamamura S, Oguchi T and Yamamoto K. Characterization of amorphous ursodeoxycholic acid prepared by spray-drying. J. Pharm. Pharmacol. 50(11), 1998 Nov, 1213-1219
61.Chen R, Tagawa M, Hoshi N, Ogura T, Okamoto H and Danjo K. Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique. Chem. Pharm. Bull. 52(9), 2004 Sep, 1066-1070.
62.Tanno, Fumie, Nishiyama and Yuichi. Process for producing a pharmaceutical solid preparation containing a poorly soluble drug. United states patent No. 6872336.
63.Takeuchi H, Nagira S, Yamamoto H and Kawashima Y. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. Int. J. Pharm. 293,2005, 155 164.
64.Takeuchi H, Nagira S, Yamamoto H and Kawashima Y. Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method. Powder technology141, 2004,187-195.
65.Ghebremeskel A N, Vemavarapu C and Lodaya M. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer surfactant combinations using solubility parameters and testing the processability. Int. J. Pharm. 328, 2007, 119 -129.
66.Zhang R and Somasundaran P. Advances in adsorption of surfactants and their mixtures at solid/solution interfaces. Advances in colloid and interface science 123-126,2006,213-229.
67.Karatas A, YÃ¼ksel N and T Baykara. Improved solubility and dissolution rate of piroxicam usingGelucire 44/14 and Labrasol . Il Farmaco 60, 2005, 777-782.
68.YÃ¼kse N, Karatas A, YalcÂ¸Ã½n OÂ¨ zkan, Ayhan SavasÂ¸er, Sibel A. OÂ¨ zkan and Baykara T. Enhanced bioavailability of piroxicam using Gelucire 44/14 and Labrasol: in vitro and in vivo evaluation. Eur. J. Pharm. Biopharm. 56, 2003, 453-459.
69.Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P and Mooter G Van den. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 10, 2000, 311 322.
70.Damian F, Blaton N, Kinget R and Mooter G Van den. Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K3. Int. J. Pharm. 244,2002, 87- 98.
71.Ivanova R, Lindman B and Alexandridis P. Effect of pharmaceutically acceptable glycols on the stability of the liquid crystalline gels formed by poloxamer 407 in water. J of Colloid and Interface Sci. 252, 2002,226 235.
72.Erlandsson B. Stability-indicating changes in poloxamers: the degradation of ethylene oxidepropylene oxide block copolymers at 25 and 40 Co. Polymer degradation and stabili ty 78,2002,571-575.
73.Jannin V, Pochard E and Chambin O. Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing PrecirolÂ® ATO 5. Int. J. Pharm. 309, 2006, 6- 15.
74.Chen Y, Zhang G G Z, Neilly J, Marsh K, Mawhinney D and Sanzgiri Y D. Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-6. Int. J. Pharm. 286, 2004, 69 80.
75.Ivanova R, Alexandridis P and Lindman B. Interaction of poloxamer block copolymers withÂ Â co solvents and surfactants. Colloids and Surfaces A: Physicochemical and Engineering Aspects 183 185,2001, 41 53.
76.Joshi H N, Tejwani R W, Davidovich M, Sahasrabudhe V P, Jemal M, Bathala M S, Varia S A and Serajuddin A T M. Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol Polysorbate 80 mixture. Int. J. Pharm. 269, 2004, 251 -258.
77.Sheen P C, Khetarpal V K, Cariola C.M and Â Â Rowlings C E. Formulation studies of a poorly water-soluble drug in solid dispersions to improve bioavailability. Int. J. Pharm. 118, 1995, 221-227.
78.Hohman M M, Shin M, Rutledge G and Michael P. Brennera electrospinning and electrically forced jets. II. Applications. Physics of fluids, 13(8), 2001, 2221-2236.
79.Muhrer G, Meier U, Fusaro F, Albano S and Mazzotti M. Use of compressed gasÂ precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug-polymer solid dispersions. Int. J. Pharm. 308,2006, 69-83.
80.Majerik V, Charbit G, Badens E, HorvÂ´ath G, Szokonya L, Bosc N and Teillaud E. Bioavailability enhancement of an active substance by supercritical antisolvent precipitation. of Supercritical Fluids 40,2007, 101 110.
81.Taki S, Badens E and Charbit G. Controlled release system formed by supercritical anti-solvent coprecipitation of a herbicide and a biodegradableÂ polymer. J of Supercritical Fluids 21,2001,61 70.
82.Manna L, Banchero M, Solta D, Ferri A, Ronchetii S and Sicrdi S. Impregnation of PVPÂ microparticles with ketoprofen in the presence of supercritical CO2. J of Supercritical Fluids 2006 article in press.
83.Dohrn R, Bertakis E, Behrend O, Voutsas E and Tassios D. Melting point depression by using supercritical CO2 for a novel melt dipersion micronization process. J of Molecular Liquids 131- 132, 2007, 53-59.