SOLID DISPERSION TECHNOLOGY: RECENT ADVANCEMENTS IN THE DELIVERY OF VARIOUS PHYTOCONSTITUENTS

SOLID DISPERSION TECHNOLOGY: RECENT ADVANCEMENTS IN THE DELIVERY OF VARIOUS PHYTOCONSTITUENTS

Rakesh Pahwa ¹, Umang Kataria ¹, A. C. Rana ¹, Rekha Rao ² and Sanju Nanda^*3

Institute of Pharmaceutical Sciences ¹, Kurukshetra University, Kurukshetra-136119, Haryana, India

Department of Pharmaceutical Sciences ², Guru Jambheshwar University of Science and Technology, Hisar-125001, Haryana, India

Department of Pharmaceutical Sciences ³, Maharshi Dayanand University, Rohtak-124001, Haryana, India

ABSTRACT: Nature is an eminent source of potential therapeutic drugs, however; most of the herbal bioactives are left unexploited as precise remedies due to lack of appropriate formulation design and development. Pharmacological interventions of herbal molecules may often be limited due to insufficient solubility, bioavailability as well as instability aspects and it remains one of the most challenging facet for pharmaceutical scientists worldwide. Solid dispersion is one of the well established and convenient techniques for improving the oral absorption of drugs with poor aqueous solubility and dissolution rate. The objective of present study is to enlighten the role of solid dispersion approach for enhancement of solubility and bioavailability profile of various natural moieties. The manuscript also aims to summarize the important features of solid dispersions, carriers utilized, classification, preparation methods and characterization parameters. Numerous and significant research findings in the vistas of phytoconstitutents based solid dispersions are also discussed.

Solid dispersion, Solubility enhancement, Characterization aspects, Phytoconstituents

INTRODUCTION: Herb is a plant or part of a plant valued for its medicinal, aromatic or savoury qualities¹. These botanicals are known to contain one or many chemical constituents that may have significant therapeutic purposes ². The belief that natural medicines are much safer than synthetic drugs has gained popularity in recent years and led to tremendous growth of various phytopharmaceutical usage. Herbal medicines are also now in great demand in the developing world for primary healthcare and recent developments in the avenue of herbal drug delivery efficiently manage several human diseases ³.

These natural drugs are safe, inexpensive, better cultural acceptability, better compatibility, minimal side effects and have fascinated several scientific community worldwide towards herbal drug technological procedures ^{4, 5}. However, they require significantly more research endeavours for their rational approach and effective utilization in the drug discovery pipeline of natural drugs. Moreover, scientific validation emphasizing on safety and efficacy profile of botanical extracts and compounding is also necessary and can open new doors for herbal drug technology.

The herbal drug technologies have facilitated the drug utilization of phytoconstituents and bioactives in a more precised manner ⁶. Interest in natural product research has been rekindled by discoveries of various novel natural molecules. But, therapeutic potential of natural molecules may often be limited by low solubility, bioavailability and instability associated with herbals. Exploration of solid dispersion technique provides various advantages including enhancement of solubility and bioavailability, protection from toxicity, enhancement of stability, sustained delivery, protection from physical and chemical degradation etc ⁷.

Hence, there is a great potential for valuable herbal drugs to be formulated into solid dispersions which subsequently facilitates the safe, effective and convenient delivery of natural bioactive constituents in an efficient and controlled manner ⁸.

The oral route of drug administration is the most common and preferred method of delivery due to convenience and ease of administration ^{9, 10}. Among the various dosage forms available for oral administration, solid dosage forms have many advantages over other types of dosage forms owing to greater stability, diminutive bulk, accurate dosage and easy production.

Therefore, most of the new molecules under development are intended to be utilized as solid that originate an effective in vivo plasma concentration after oral administration ¹¹. But, the major problem associated with most of the drugs is inadequate solubility in biological fluids that ultimately limits their bioavailability and utility after oral administration ¹². The natural products with therapeutic benefits like curcumin¹³, dihydroartimisinin ¹⁴, biochanin A ¹⁵ are poorly water soluble and not well absorbed after oral administration which detract them from inherent efficacy ¹⁶. Moreover, low aqueous solubility and membrane permeability of a drug molecule consequently retard the drug absorption from gastrointestinal tract ¹¹.

The insufficient solubility may be due to high crystallinity/high melting point of pharmacologically active compounds that leads to formation of zwitterion, insoluble salts and H-bonding network. Hydrophobicity/High log P is another reason for inadequate solubility due to lack of ionizable groups and high molecular weight^{17, 18}.

The drugs can be categorized into four classes according to biopharmaceutical classification system depending on in vitro solubility and in vivo permeability data as depicted in Table 1^19-21.

TABLE 1: BIOPHARMACEUTICAL CLASSIFICATION SYSTEM 

Among the four classes, class II drugs show poor solubility and high permeability. Therefore, their low ability to dissolve is a limitation to their overall rate and extent of absorption over their ability to permeate through the membrane. Hence, the formulation design for class II compounds should focus on the enhancement of aqueous solubility or dissolution rate ¹⁹. Once these drugs dissolve, they rapidly pass through biological membranes such as the gastrointestinal wall^{13, 22}.

Development of an optimized and more bioavailable formulation of a particular drug is a herculean task ²³.  Several methods have been employed to enhance the solubility, dissolution and subsequently bioavailability of drugs with low solubility profile. Some methods comprises of particle size reduction, cyclodextrin complexation, solubilization, co-solvency, solid dispersions, salt formation, polymorphs, solvents or hydrates, pro-drug approach, multiparticulate systems, etc. However each of these methods has some practical limitation ²⁴.

Solid dispersion is one of the most successful and convenient strategic approaches to improve drug release of poorly soluble drugs ¹¹. This technique molecularly disperses the drug into polymeric carrier, and release rate depends on the nature of carrier ^{13, 25}.

Solid dispersions: Solid dispersions have been traditionally used as an effective method to improve the dissolution property and bioavailability of poorly water soluble drugs ²⁶. In 1961, Sekiguchi and Obi first proposed the utilization of solid dispersions to increase the dissolution and oral absorption of such drugs²⁷. Earlier studies also reveal that solid dispersion systems increased the drug dissolution due to improved solubility, wet ability and dispersability using hydrophilic carriers ²⁶. The development of solid dispersion as a practically viable method to enhance bioavailability of poorly water soluble drugs overcame the limitations of several other approaches such as a salt formation, solubilization by co solvents and particle size reduction ²⁸.

The term solid dispersions refer to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles based on their molecular arrangement²¹. Chiou and Riegelman defined the term solid dispersions as, 'a dispersion involving the formation of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixtures' ^{9, 29}. The dissolution of the drug has been enhanced by dispersing a poorly soluble drug in a highly soluble solid hydrophilic matrix¹⁷.

Carriers explored for preparation: The choice of carrier has a tremendous impact on the success rate of the solid dispersion strategies. Following criteria should be considered during selection of carriers:

High water solubility-improves wettability and enhances dissolution.

• High glass transition point-improve stability.
• Minimal water uptake.
• Soluble in common solvent with drug-solvent evaporation.
• Relatively low melting point-melting process.
• Capable of forming a solid solution with the drug-similar solubility parameter ¹⁶.

The excipients employed as carriers in solid dispersions and their nature has been summarized in Table 2 ^{30, 31}.

 TABLE 2: CARRIERS USED IN SOLID DISPERSION

Mechanism of dissolution: The enhanced and effective dissolution rate of various drugs from prepared solid dispersions is based on different mechanisms described in the following section. These mechanisms include: (a) wetting of the drug is improved by direct contact of the drug with the hydrophilic polymeric material, (b) the saturated concentration around small particles is higher than around large particles ³², (c) the surface area is increased, and (d) the drug has higher energy in amorphous state than in the crystalline state through which the saturated concentration is increased ³³. Therefore, solid dispersion upgrades the bioavailability of poorly soluble drugs by increasing the drug dissolution rate and their saturated solubility in the gastrointestinal fluids ³⁴.

 Advantages: The solid dispersions provide the myriad spectrum of desired characteristics for effective delivery of drugs. Various advantages of solid dispersions are mentioned in the subsequent text: ^{16, 35-37}

• Improved wettability results in increased solubility.
• Particles having higher porosity. Increase in porosity influence carrier properties and increases the drug release profile.
• Amorphous state of drug leads to enhancement in drug release.
• Pre-systemic metabolism is reduced due to increase in dissolution rate and absorption.
• Liquid form of drug can be transformed into solid form.
• Solid dispersion method is usually preferred over other particle size reducing techniques to enhance the solubility because other size reduction techniques may not cause enough enhancements in drug solubility and improvement in bioavailability.
• Particle size reduction in solid dispersion leads to increased surface area which causes increase in dissolution rate and hence subsequently bioavailability is improved.
• By changing water solubility, drug bioavailability can also be increased.

Limitations: Despite of various merits of solid dispersion techniques, there are some limitations of solid dispersions and these are enumerated in the following section: ^{16, 36-38}

• Moisture and temperature may affect physical characteristics of solid dispersions.
• Tackiness property of solid dispersions, sometimes makes it difficult to handle.
• Stability problem of vehicle and drug may occur.
• Reproducibility of physicochemical characteristics.
• Large amount of carrier is required to achieve good dissolution.
• During storage of solid dispersion, many problems may be encountered such as phase separation, conversion of amorphous to crystalline form and crystal growth due to which decrease in solubility, dissolution and bioavailability occurs.
• Various synthetic polymers such as polyvinyl pyrrolidone, polyethylene glycol, mannitol are used which are water soluble and has low melting point and are used in large amount but these occasionally show less dissolution enhancement.
• Method of preparation is expensive.

Classification:

Considering mutual spatial arrangement of individual components and their state ³⁹, various types of solid dispersions can be distinguished as presented in Fig. 1 ^{36, 40}. The type of solid dispersion and its dissolution behaviour are strongly influenced by physicochemical properties of drug and carrier and the used production process ⁴¹.  

FIG. 1: CLASSIFICATION OF SOLID DISPERSIONS

Manufacturing process: The subsequent section is a brief preface of the various techniques widely accepted for formulation of solid dispersions.

1. Melting (Fusion method): Melting method comprises of heating all components above their melting or glass transition temperatures, followed by mixing and cooling ⁴². The uniformly mixed melted mass is allowed to cool at room temperature or under cool conditions. The cooling rate may have great impact on the characteristics and

stability of solid dispersion ²⁴. For cooling and solidification, various processes such as ice bath agitation ^{43, 44}, solidification on petri dishes at room temperature inside a dessicator ^{45, 46}, spreading on plates placed over dry ice ⁴⁷, immersion in liquid nitrogen ⁴⁸ or stored in dessicator ^{49, 50} were used ⁵¹. The most important requirement with this method is that drug and carrier should be stable at the process temperature. Carrier should have a lower melting point (T_m) or high glass transition temperature (T_g) than the drug practically to allow a more practically processing temperature and decreases the potential of drug degradation ⁴¹.

The method is advantageous due to its simplicity and economy ²⁹. In addition, a super saturation of a solute or drug in a system can often be obtained by quenching the melt rapidly from a high temperature ⁵². The major disadvantage of this method is that the texture of solid dispersion after cooling is quite hard. Therefore, size reduction of the solid dispersion may be difficult ⁴¹.

2. Solvent method: Solvent method aims to dissolve both the drug and carrier in organic solvent, followed by evaporating the solvent. Solvent is allowed to evaporate by various processes including vacuum drying ^{53, 54}, heating on a hot plate ⁵⁵, using rotary evaporator ⁵⁶, a stream of nitrogen ⁵⁷, spray drying ⁵⁸, freeze drying ⁵⁹ and using supercritical fluids ^{60, 61}.

The advantage of this method is that thermal decomposition of drugs or carriers can be prevented because of the low temperature required for the evaporation of organic solvents ²⁹.  The major challenge in the preparation of solid dispersion by solvent method is to mix both the drug and the matrix in one solution, which is difficult when they differ significantly in polarity. To minimize the drug particle size in solid dispersion, the drug and matrix have to be dispersed in the solvent as fine as possible, preferably drug and matrix material are in the dissolved state in one solution ^{40, 62}.

3. Melting solvent method: The method is a combination of melting method and solvent evaporation method ⁶³. It is performed by dissolving the drug in a suitable solvent and mixing of this solution with the molten carrier followed by cooling, resulting in solidification ^{64, 65}. Such a unique method possesses the advantages of both the melting and solvent methods. Unfortunately, from a practical standpoint, it is only limited to drugs with low therapeutic dose, e.g. below 50 mg ²⁹.

4. Hot melt extrusion: Hot melt extrusion is a combination of melting and a mechanical process in which the drug, polymer and optionally plasticizer are mixed and melted under controlled conditions of temperature and shear forces. The mass of co-melts is mixed with the help of transport screws and extruded through a die plate, yielding solid dispersions ⁴¹. This method offers the potential to shape the heated drug-matrix mixture into implants, ophthalmic inserts, or oral dosage forms ^{40, 66}. Metrex^® process is a technology based on hot melt extrusions and applied for the development of a ritonavir-lopinavir combination tablet with improved dissolution characteristics ⁴¹. Another technology based on molten substances is Meltdose^® for improving the dissolution of fenofibrate ⁴¹.

5. Spray drying method: In this method, where a solution of drug and carrier is evaporated by spraying the solution as fine droplets into a chamber under controlled conditions of heat, humidity and air flow ⁶³. It is cheap, fast and a one-step process and is widely used for processing solutions, emulsions, suspensions into powders, efficiently controlling size, density and morphology of the particles ⁶⁷. However, the formation of a sticky product at the outlet of spray drier may occur ⁴¹.

6. Freeze drying method: Freeze drying consists of three successive steps: freezing, primary drying and secondary drying. A sample to be freeze dried consists of a drug, excipients and one or more solvents ⁴¹. High freezing rates can be achieved by using cryogenic liquids such as liquid nitrogen. Either vials containing the solution can be immersed in the cryogenic liquid or the solution is sprayed directly into the cryogenic liquid ⁴¹. It is preferred for the preparation of solid dispersion of thermolabile materials but also has a disadvantage of being time consuming and expensive process²⁴.

7. Supercritical fluid technology: Supercritical fluids can dissolve nonvolatile solvents, with the critical point of carbon dioxide; the most widely used supercritical fluid. This technique offers tremendous potential as it is safe, environmentally friendly and economical ⁶⁸. Supercritical micronization processes such as rapid expansion of a supercritical solution ⁶⁹, gas anti solvent process ^{70, 71}, particles from gas saturated solutions and precipitation with compressed fluid antisolvent ⁷² have gained increasing attention and may be considered as interesting alternatives and most effective processes for microionization of solid dispersions ⁷³.

8. Kneading method: the physical mixture of drug and carrier is triturated to thick paste utilizing small volume of solvent. The solvent used can be organic (alcohol, dichloromethane, acetone) or aqueous or mixture thereof. The kneaded paste is dried in an oven and the dried mass is pulverized and subsequently stored in dessicator. This process is economical but residual solvent may be an issue ²⁴.

Characterization aspects: Characterization of solid dispersion is intended for identification of physical state (amorphous or crystalline), various properties (such as particle size, degree of crystallinity, shape, morphology etc.), drug-carrier interactions, drug-carrier miscibility, dissolution testing and stability parameters.

Various techniques employed in the characterization of solid dispersions includes microscopic techniques (polarized light optical microscopy, scanning electron microscopy, atomic force microscopy and hot stage microscopy); spectroscopic techniques (fourier transform infrared spectroscopy, H¹ nuclear magnetic resonance, Raman spectroscopy); thermal analysis technique (conventional differential scanning calorimetry, temperature modulated differential scanning calorimetry, isothermal microcalorimetry) and various other miscellaneous techniques such as powder X-ray diffraction, water vapour sorption etc ^{29, 40, 74-85}.

Careful analysis of literature on solid dispersions provides prominence to their success in enhancing solubility, dissolution and subsequently bioavailability of several natural moieties. Table 3 highlights the favourable outcomes and reported method of preparations of various solid dispersions of natural constituents. Several research endeavour have been carried out by large number of investigators worldwide in order to enhance the dissolution rate and thereby bioavailability of diverse naturally active constituents.

TABLE 3: LIST OF NATURAL DRUGS INCORPORATED INTO SOLID DISPERSIONS

Therefore, several scientific advancements have been undertaken in the avenue of phytoconstituents based solid dispersion technology which reflects the successful and effective utilization of various natural drugs.

CONCLUSION: The naturally active constituents have tremendous pharmacological significance, however; their effective utilization has been limited due to various constraints such as poor solubility, bioavailability and instability. Large number of investigators across the globe developed numerous techniques to overcome several problems associated with herbal drugs. Solid dispersion technology has been explored by scientific community as an efficient and successful methodology for improving solubility profile and bioavailability of natural drugs. Moreover, it is a promising and convenient method for achieving sustained release characteristics of natural moieties.

The present manuscript is an attempt to provide an insight view on the design and development of solid dispersion of natural constituents. Furthermore, the wide availability of carriers and various preparation techniques along with characterization aspects of solid dispersions are also discussed. Despite remarkable achievements in solid dispersion technologies, this arena still has promising potential for future innovations and advancements in the delivery of various botanicals. Investigational research can also be persuaded to improve the feasibility and proper utilization of new herbal drug delivery systems. Furthermore, these exciting opportunities will also quicken the expansion of research and commercialization of this advanced approach in the fascinating arena of phytoconstituents.

ACKNOWLEDGEMENT: Professor Arun Nanda, Dean, Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, India, is duly acknowledged for his valuable suggestions in the preparation of this manuscript.

REFERENCES:

1. Kunle, Folashade O, Egharevba, Omoregie H, Ahamdu and Ochogu P: Standardization of herbal medicines-a review. International Journal of Biodiversity and Conservation 2012; 4(3): 101-112.
2. Heng MY, Tan SN, Hong Yong JW and Ong ES: Emerging green technologies for the chemical standardization of botanicals and herbal preparations. Trends in Analytical Chemistry 2013; 50: 1-10.
3. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H: Pharmacokinetics and bioavailability of herbal medicinal products. Phytomedicine 2002; 9 (Suppl 3): 1-33.
4. Bodhisattwa M, Nagori BP, Singh R, Kumar P and Upadhyay N: Recent trends in herbal drugs: a review. International Journal of Drug Research and Technology 2011; 1(1): 17-25.
5. Sanjoy KP and Yogeshwer S: Herbal medicine: current status and the future. Asian Pacific Journal of Cancer Prevention 2003; 4(4): 281-288.
6. Saraf S, Shailendra S and Gupta A: Exploration of novel targets for effective extracellular matrix therapy through herbal drugs. Pharma Times 2013; 45(9): 14-20.
7. Ajazudin and Saraf S: Applications of novel drug delivery system for herbal formulations. Fitoterapia 2010; 81(7): 680-689.
8. Gowthamarajan K, Dwarampudi LP, Ramaswamy S and Suresh B: The recent surge in herbal pharmaceuticals. Pharma Times 2013; 45(9): 25-28.
9. Sonpal RN, Lalwani AN, Darji V and Patel K: Solid dispersion: an efficient tool for increasing bioavailability of poorly soluble drugs. International Journal of Pharmaceutical Sciences Review and Research 2011; 89(1): 37-52.
10. Lachman L, Liberman HA: Theory and Practice of Industrial Pharmacy, CBS Publishers & Distributors, New Delhi, Edition 3rd. 1998: 462-464.
11. Aggarwal S, Gupta GD and Chaudhary S: Solid dispersion as an eminent strategic approach in solubility enhancement of poorly soluble drugs. International Journal of Pharmaceutical Sciences and Research 2010; 1(8): 1-13.
12. Das KS, Roy S, Kalimuthu Y, Khanam J and Nanda A: Solid dispersions: an approach to enhance bioavailability of poorly water soluble drugs. International Journal of Pharmacology and Pharmaceutical Technology 2011; 1(1): 37-46.
13. Wan S, Sun Y, Qi X and Tan F: Improved bioavailability of poorly soluble drug curcumin in cellulose acetate solid dispersion. AAPS PharmSciTech 2012; 13(1): 149-156.
14. Ansari MT, Batty K, Iqbal I and Sunderland VB: Improving solubility and bioavailability of dihydroartemisinin by solid dispersion and inclusion complex. Archives of Pharmacal Research 2011; 34(5): 757-765.
15. Han HK, Lee BJ and Lee HK. Enhanced dissolution and bioavailability of biochanin A via the preparation of solid dispersion: in vitro and in vivo International Journal of Pharmaceutics 2011; 415(1): 89-94.
16. Tiwari R, Tiwari G, Srivastava B and Rai A: Solid dispersions: an overview to modify bioavailability of poorly water soluble drugs. International Journal of PharmTech Research 2009; 1(4): 1338-1349.
17. Kumar P and Arora V: Solid dispersion: a review. Journal of Pharmaceutical and Scientific Innovation 2012; 1(3): 27-34.
18. Tong WQ: Pharmaceutical Preformulation. Integrated drug development process 2012; Available from http://www.pharmacy.utah.edu/pharmaceutics/pdf/Preformulation.pdf Accessed on 21-05-2014.
19. Giri TK, Alexander A and Tripathi DK: Physicochemical classification and formulation development of solid dispersion of poorly water soluble drugs: an updated review. International Journal of Pharmaceutical and Biological Archives 2010; 1(6): 309-324.
20. Amidon GL, Lennernas H, Shah VP and Crison JR: A theoretical basis for a biopharmaceutical drug classification: correlation of in vitro drug product dissolution and in vivo Pharmacal Research 1995; 12(3): 413-420.
21. Kumar BP, Rao S, Murthy KVR, Sahu RK and Ramu B: Solid dispersion: a tool for enhancing bioavailability of poorly soluble drugs. Journal of Chemical and Pharmaceutical Sciences 2011; 4(4): 170-179.
22. Visser MR, Baet L, Klooster GV, Schueller L, Geldof M, Vanwelkenhuysen I, Kock HD, Meyer SD, Frijlink HW, Rosier J and Hinrichs WLJ: Inulin solid dispersion technology to improve the absorption of the BCS class IV drug TMC240. European Journal of Pharmaceutics and Biopharmaceutics 2010; 74(2): 233-238.
23. Jishnu V, Sahadevan JT and Gilhotra RM: A basic insight into the stability and manufacturing aspects of solid dispersions. Chronicles of Young Scientists 2012; 3(2): 95-105.
24. Alam MA, Ali R, Al-Jenoobi FI and Al- Mohizea AM: Solid dispersion: a strategy for poorly aqueous soluble drugs and technology updates. Expert Opinion on Drug Delivery 2012; 9(11): 1419-1440.
25. Hernandez JI, Ghaly ES, Malave A and Marti A: Controlled-release matrix of acetaminophen-ethyl cellulose solid dispersion. Drug Development and Industrial Pharmacy 1994; 20(7): 1253-1265.
26. Shinde SS, Patil SS, Mevekari FI and Satpute AS: An approach for solubility enhancement: solid dispersion. International Journal of Advances in Pharmaceutical Sciences 2010; 1(3): 299-308.
27. Tyagi R and Dhillon V: Solid dispersions: a fruitful approach for improving the solubility and dissolution rate of poorly soluble drugs. Journal of Drug Delivery and Therapeutics 2012; 2(4): 5-14.
28. Patidar K, Soni M, Sharma KD and Jain KS: Solid dispersion: approaches technology involved, unmet need and challenges. Drug Invention Today 2010; 2(7): 349-357.
29. Chiou WL and Riegelman S: Pharmaceutical applications of solid dispersion system. Journal of Pharmaceutical Sciences 1971; 60(9): 1281-1302.
30. Sachan NK and Pushkar S: Solid dispersion: an industrially feasible alternative approach to formulate brick dust molecules. Bulletin of Pharmaceutical Research 2011; 1(1): 75-80.
31. Bowmik D, Harish G, Duraivel S, Kumar BP, Raghuvanshi V and Sampath KP: Solid dispersion-an approach to enhance the dissolution rate of poorly water soluble drugs. The Pharma Innovation Journal 2012; 1(12): 24-38.
32. Keck CM and Muller RH: Drug nanocrystals of poorly soluble drugs produced by high pressure homogenization. European Journal of Pharmaceutics and Biopharmaceutics 2006; 62(1): 3-16.
33. Junghanns AH and Muller RH: Nanocrystals technology, drug delivery and clinical applications. International Journal of Nanomedicine 2008; 3(3): 295-309.
34. Hang Yu, Roshab KS, Pushp RN, Yoon GK and Hoo KC: Enhancement of solubility and dissolution rate of cryptotanshinone, tanshinone and tanshinone II extracted from Salvia miltiorrhiza. Archives of Pharmacal Research 2012; 35(8): 1457-1464.
35. Kumar S, Malviya R and Sharma PK: Solid dispersion: Pharmaceutical technology for the improvement of various physical characteristics of active pharmaceutical ingredients. African Journal of Basic and Applied Sciences 2011; 3(4): 116-125.
36. Dhiman S, Kaur P and Arora S: Solid dispersion: opportunity in drug delivery system. Drug Invention Today 2012; 4(10): 478-486.
37. Verma S, Rawat A, Kaul M and Saini S: Solid dispersion-a strategy for solubility enhancement. International Journal of Pharmacy and Technology 2011; 3(2): 1062-1099.
38. Kalia A and Poddar M: Solid dispersions: an approach towards enhancing dissolution rate. International Journal of Pharmacy and Pharmaceutical Sciences 2011; 3(4): 9-19.
39. Karolewicz B, Agata G, Sandra P, Artur O, Janusz P and Plaksej EZ: Solid dispersion in pharmaceutical technology. Part I. Classification and methods to obtain solid dispersions. Polymers in Medicine 2012; 42(1): 17-27.
40. Dhirendra, Lewis KS, Udupa N and Atin K: Solid dispersion: a review. Pakistan Journal of Pharmaceutical Sciences 2009; 22(2): 234-246.
41. Srinarong P, Hans W, Hendrick WF and Hinrichs WL: Improved dissolution behaviour of lipophilic drugs by solid dispersions: the production process as starting point for formulation consideration. Expert Opinion on Drug Delivery 2011; 8(9): 1121-1140.
42. Sandrien J and Mooter GVD: Physical chemistry of solid dispersions. Journal of Pharmacy and Pharmacology 2009; 61(12): 1571-1586.
43. Sekiguchi K and Obi N: Studies on absorption of eutectic mixture. II Absorption of fused conglomerates of chloramphenicol and urea in rabbits. Chemical and Pharmaceutical Bulletin 1964; 12: 134-144.
44. Pokharkar VB, Mandpe LP, Padamwar MN, Ambike AA, Mahadik KR and Paradkar A: Development and characterization and stabilization of amorphous form of a low T_g Powder Technology 2006; 167(1): 20-25.
45. Li, FQ, Jin-Hong-Hu, Jia-Xin Deng, Hua Su, Shu Xu and Ji-Yong Liu: In vitro controlled release of sodium ferulate from compritol 888 ATO based matrix tablets. International Journal of Pharmaceutics 2006; 324(2): 152-157.
46. Owusu-Ababio: Comparative dissolution studies for mefenamic acid polyethylene glycol solid dispersion systems and tablets. Pharmaceutical Development and Technology 1998; 3 (3): 405-412.
47. Timko RJ and Lordi NG: Thermal characterization of citric acid solid dispersions with benzoic acid and phenobarbital. Journal of Pharmaceutical Sciences 1979; 68(5): 601-605.
48. Yao WW, Bai TC, Sun JP, Zhu CW, Jie H and Zhang HL: Thermodynamic properties for the system of silybin and polyethylene glycol 6000. Thermochimica Acta 2005; 437(1-5): 17-20.
49. Vippagunta SR, Zeren W, Stefanie H and Steven LK: Factors affecting the formulation of eutectic solid dispersions and their dissolution behaviour. Journal of Pharmaceutical Sciences 2007; 96(2): 294-304.
50. Lin CW and Cham TM: Effect of particle size on available surface area of nifedipine from nifedipine-polyethylene glycol 6000 solid dispersions. International Journal of Pharmaceutics 1996; 127(2): 261-272.
51. Vasconcelos T, Bruno S and Paulo C: Solid dispersion as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 2007; 12(23/24): 1068-1075.
52. Moore WJ, Physical Chemistry, Prentice-Hall, Englewood Cliffs. N. J., Fourth Edition 1963.
53. Karavs E, Georgarakis E, and Bikaris D: Application of PVP/HPMC miscible blends with enhanced mucoadhesive properties for adjusting drug release in predictable pulsatile chronotherapeutics. European Journal of Pharmaceutics and Biopharmaceutics 2006; 64(1): 115-126.
54. Wang X, Michoel A and Mooter DG: Solid state characteristics of ternary solid dispersion composed of PVP VA64, Myrj 52 and itraconazole. International Journal of Pharmaceutics 2005; 303(1-2): 54-61.
55. Desai J, Alexander K and Riga A: Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. International Journal of Pharmaceutics 2006; 308(1-2): 115-123.
56. Ceballos, Cirri AM, Maestrelli F, Corti G and Mura P: Influence of formulation and process variables on in vitro release of theophylline from directly compressed Eudragit matrix tablets. IL Farmaco 2005; 60(11-12): 913-918.
57. Prabhu S, Ortega M and Ma C: Novel lipid based formulations enhancing the in vitro dissolution and permeability characteristics of a poorly water soluble model drug, piroxicam. International Journal of Pharmaceutics 2005; 301(1-2): 209-216.
58. Mooter GV, Weuts I, Rider TD and Blaton N: Evaluation of Inutec SPI as a new carrier in the formulation of solid dispersion of poorly water soluble drugs. International Journal of Pharmaceutics 2006; 316(1-2): 1-6.
59. Drooge VDJ, Hinrichs WLJ, Visser MR and Frijlink HW: Characterization of the molecular dispersion of drugs in glassy solid dispersion at the nano meter scale, using differential scanning calorimetry and gravimetric water vapour sorption technique. International Journal of Pharmaceutics 2006; 310(1-2): 220-229.
60. Won DH, Kim MS, Lee S, Park JS and Hwang SJ: Improved physicochemical characteristics of felodipine solid dispersion particles by superficial anti solvent precipitation process. International Journal of Pharmaceutics 2005; 301(1-2): 199-208.
61. Park JH, Chun MK, Cho H, Choi HK: Solid dispersion as a strategy to improve drug bioavailability. Korean Society for Biotechnology and Bioengineering 2011; 26(4): 283-292.
62. Leuner C and Jennifer D: Improving drug solubility for oral drug delivery using solid dispersions. European Journal of Pharmceutics and Biopharmaceutics 2000; 50(1): 47-60.
63. Giri TK, Kumar K, Alexander A, Ajazuddin, Badwaik H and Dulal KT: A novel and alternative approach to controlled release drug delivery system based on solid dispersion technique. Bulletin of Faculty of Pharmacy, Cairo University 2012; 50(2): 147-159.
64. Vera N, Vigra MD and Cadorniga R: Solid dispersions of oxodipine/PEG 6000 characterization and dissolution study. S.T.P. Pharma Sciences 1991; 1: 125-129.
65. Fernandez M, Rodriguez IC, Margarit MV and Cerezo A: Characterization of solid dispersions of piroxicam/poly-(ethylene glycol) 4000. International Journal of Pharmaceutics 1992; 84(2): 197-202.
66. Breitenbach J: Melt extrusion: from process to drug delivery technology. European Journal of Pharmaceutics and Biopharmaceutics 2002; 54(2): 107-117.
67. Bikaris DN: Solid dispersion, Part I: recent evaluation and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water soluble drugs. Expert Opinion on Drug Delivery; 2011: 8(11): 1501-1519.
68. Karanth H, Shenoy VS and Murthy RR: Industrially feasible alternative approach in manufacture of solid dispersion: A technical report. AAPS PharmSciTech 2006; 7(4): 31-38.
69. Vemavarapu C, Mollan MJ and Needham TE: Coprecipitation of pharmaceutical actives and their structurally related additives by the RESS process. Powder Technology 2009; 189(3): 444-453.
70. Cho E, Cho W and Cha KH: Enhanced dissolution of megestrol acetate microcrystal prepared by antisolvent precipitation process using hydrophilic additives. International Journal of Pharmaceutics 2010; 396(1-2): 91-98.
71. Galia A, Scialdone O and Filardo G: A one pot method to enhance dissolution rate of low solubility drug molecules using dispersion polymerization in supercritical carbon dioxide. International Journal of Pharmaceutics 2009; 377(1-2): 60-69.
72. Wu Ke, Li J, Wang W and Winstead DA: Formation and characterization of solid dispersions of piroxicam and PVP using spray drying and precipitation with compressed antisolvent. Journal of Pharmaceutical Sciences 2009; 98(7): 2422-2431.
73. Bikaris DN: Solid dispersion, Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water soluble drugs. Expert Opinion on Drug Delivery 2011; 8(12): 1663-1680.
74. Karolewicz B, Agata G, Sandra P, Artur O, Janusz P and Plaksej EZ: Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their applications. Polymers in Medicine 2012; 42(2): 97-107.
75. Ansari MT, Pervez H, Shehzad MT, Saeed-ul-Hassan S, Mehmood Z, Shah SN, Razi MT and Murtaza G: Improved physicochemical characteristics of artemisinin using succinic acid. Acta Poloniae Pharmaceutica-Drug Research 2014; 71(3): 451-462
76. Tian B, Zhang L, Pan Z, Gou J, Zhang Y and Tang X: A comparison of the effect of temperature and moisture on the solid dispersions: aging and crystallization. International Journal of Pharmaceutics 2014; 475(1-2): 385-392.
77. Sarode AL, Malekar SA, Cote C and Worthen DR: Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydrate Polymers 2014; 112: 512-519.
78. Prasad D, Chauhan H and Atef E: Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects. Journal of Pharmaceutical Sciences 2014; 103(11): 3511-3523.
79. Skiba M, Skiba M, Milon N, Bounoure F and Fessi H: Preparation and characterization of amorphous solid dispersions of nimesulide in cyclodextrin copolymers. J Nanoscience and Nanotechnology 2014; 14(4): 2772-2779.
80. Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, Talekar M, Sharma M and Garg S: Development of solid dispersion systems of dapivirine to enhance its solubility. Current Drug Delivery 2013; 10(3): 309-316.
81. Kumar S and Gupta SK: Effect of excipients on dissolution enhancement of aceclofenac solid dispersions studied using response surface methodology: a technical note. Archives of Pharmacal Research 2014; 37(3): 340-351.
82. Barmpalexis P, Kachrimanis K and Georgarakis E: Physicochemical characterization of nimodipine-polyethylene glycol solid dispersion systems. Drug Development and Industrial Pharmacy 2014; 40(7): 886-895.
83. Zhong L, Zhu X, Luo X and Su W: Dissolution properties and physical characterization of telmisartan-chitosan solid dispersions prepared by mechanochemical activation. AAPS PharmSciTech 2013; 14(2): 541-550.
84. Patel GC, Asodaria KV, Patel HP and Shah DR: Formulation and in vivo hypoglycemic effect of glipizide solid dispersion. Current Drug Delivery 2012; 9(4): 395-404.
85. Khan S, Batchelor H, Hanson P, Saleem IY, Perrie Y and Mohammed AR: Dissolution rate enhancement, in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions. Drug Development and Industrial Pharmacy 2013; 39(5): 704-715.
86. Shen Y, Lu F, Hou, Shen Y and Guo S: Incorporation of paclitaxel solid dispersion with poloxamer 188 or polyethylene glycol to tune drug release from poly(e-caprolactone) films. Drug Development and Industrial Pharmacy 2013; 39(8): 1187-1196.
87. Luo, Yanfei, Lishuang Xu, Ming Xu, Xiaoguang Tao, Ruiting Ai, and Xing T: Improvement of dissolution and bioavailability of ginsenosides by hot melt extrusion and cogrinding. Drug Development and Industrial Pharmacy 2013; 39(1): 109-116.
88. Jiang Y, Zhang Z, Lu Y, Ma T and Jia X. Study on solid dispersion of binary vector of tanshinone II A. China Journal of Chinese Materia Medica 2012; 37(10): 1383-1387.
89. Thakral NK, Ray AR, Bar Shalom D, Erikson AH and Majumdar DK: Soluplus solubilized citrated camptothecin-a potential drug delivery strategy in colon cancer. AAPS PharmSciTech 2012; 13(1): 59-66.
90. Xu H Zhang T, Yang H, Xiao X, Bian Y, Si D and Liu C: Preparation of evodiamine solid dispersions and its pharmacokinetic. Indian Journal of Pharmaceutical Sciences 2011; 73(3): 276-281.
91. Planinsek O, Kovacic B and Vrecer F: Carvedilol dissolution improvement by preparation of solid dispersion with porous silica. International Journal of Pharmaceutics 2011; 406(1-2): 41-48.
92. Kakran M, Sahoa NG and Li L: Dissolution enhancement of quercetin through nano fabrication, complexation and solid dispersion. Colloid Surfaces B: Biointerfaces 2011; 88(1): 121-130.
93. Dalwadi S, Tejal S, Thakkar V and Tejal G: Silymarin- solid dispersions: characterization and influence of preparation methods on dissolution. Acta Pharmaceutica 2010; 60(4): 427-443.
94. Ansari MT, Karim S, Ranjha NM, Shah NH and Muhammad S: Physicochemical characterization of artemether solid dispersions with hydrophillic carriers by freeze dried and melt methods. Archives of Pharmacal Research 2010; 33(6): 901-910.
95. Ansari MT and Sunderland VB: Solid dispersion of dihyroartemisnin in polyvinyl pyrrolidone. Archives of Pharmacal Research 2008; 31(3): 390-398.
96. Onoue, Satomi, Haruki T, Yohei K, Yoshiki S, Junya H, Barbara T and Shizuo Yamada: Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. Journal of Pharmaceutical Sciences 2010; 99(4): 1871-1881.
97. Yao L, Deng KY and Luo JB: Preparation and in vitro dissolution of solid dispersion of cinnamon oil, Nan Fang Yi Ke Da Xue Xue Bao 2008; 28(1): 52-53.
98. Oda M, Sato M, Yagi N, Ohno K, Miyazaki S, Watannabe S and Takada M: Preparation and evaluation of solid dispersions of pilocarpine hydrochloride for alleviation of xerostomia. Yakugaku Zasshi 1997; 117(1): 59-64.
99. Shah, Jaymin C, Jivn R. Chen and Diana Chow: Preformulation study of etoposide II: Increased solubility and dissolution rate by solid-solid dispersion. International Journal of Pharmaceutics 1995; 113(1): 103-111.
    

    ---

    How to cite this article:

    Pahwa R, Kataria U, Rana AC, Rao R and Nanda S: Solid Dispersion Technology: Recent Advancements in the Delivery of Various Phytoconstituents. Int J Pharm Sci Res 2015; 6(2): 510-20.doi: 10.13040/IJPSR.0975-8232.6 (2).510-20.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---