SOLID DISPERSION TECHNOLOGY: RECENT ADVANCEMENTS IN THE DELIVERY OF VARIOUS PHYTOCONSTITUENTSHTML Full Text
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 weight17, 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 119-21.
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 wall13, 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
|1.||Dextrose, Sucrose, Lactose, Sorbitol, Maltose, Mannitol, Galactose||Sugars|
|2.||Citric acid, Succinic acid, Tartaric acid||Acids|
|3.||Povidone, Polyethylene glycol, Hydroxyl propyl methyl cellulose, Methyl cellulose, Hydroxy ethyl cellulose, Pectin, Galactomannan||Polymeric material|
|4.||Polyoxyethylene stearate, Tweens, Spans, Gelucire 44/14, Pluronic F68||Surfactants|
|5.||Sodium acetate, Sodium-o-hydroxy benzoate, Sodium-p-hydroxybenzoate||Hydrotropes|
|6.||Urea, Hydroxyalkylxanthines, Silica gel, Sodium chloride, Microcrystalline cellulose||Miscellaneous|
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.
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.
- 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 (Tm) or high glass transition temperature (Tg) 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
|S. No.||Natural drugs||Ingredients utilized||Method ofPreparations||Objectives||References|
|Enhancedbioavailability, solubility and sustained release||13|
|2||Dihydroartemisinin||PVP K30, PVP K25, PVP K15 and inclusion complexes with HPβCD||Solventevaporation
|Improved solubility and bioavailability||14|
|Poloxamer 407, 2-Hydroxypropyl-β-cyclodextrin,PVP K-30, PEG 8000,PEG 3400, Microcrystalline cellulose||Solventmethod||Enhanced solubility, dissolution and bioavailability||34|
|4||Paclitaxel||Poloxamer 188, PEG||Melting method||Improved drug release||86|
|5||Ginsenosides||Sodium dodecyl sulphate||Hot melt extrusion and cogrinding||Improved dissolution and bioavailability||87|
|6||Tanshinone II A||Nano silica,Poloxamer 188||Solventmethod||Improved dissolution and stability||88|
|7||Camptothecin||Soluplus, Citric acid||Solventevaporation
|Increased aqueous solubility, stability||89|
|8||Evodiamine||PVP K-30||Solventmethod||Increased dissolution rate, improved solubility and oralbioavailability||90|
|9||Carvedilol||Porous silica (Sylysia)||Solventevaporation
|Improved wettability and dissolution||91|
|10||Quercetin||PVP, Pluronic F127||Evaporativeprecipitation
|Enhanced drug dissolution||92|
|11||Silymarin||HPMC E 15LV||Kneading, spray drying and co- precipitation methods||Improved solubility and dissolution, reduction in crystallinity||93|
|12||Artemether||PVP K25,PEG 4000||Freeze dryingand melting method||Improved rate of dissolution||94
|Improved water solubility||95|
|14||Curcumin||Hydroxypropyl cellulose SL,Hydroxypropylmethylcellulose acetate succinate||Nanomill-01 system, Freeze drying
|Improved dissolution, bioavailabilityand high photochemical stability||96|
|15||Cinnamon oil||Stearic acid,PEG 6000, Gluceryl monostearate||Melting method||Sustained release||97|
|Enhanced solubility and dissolution rate||9|
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.
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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.
Rakesh Pahwa , Umang Kataria , A. C. Rana , Rekha Rao and Sanju Nanda*
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, Haryana, India.
04 June, 2014
27 September, 2014
13 October, 2014
01 February, 2015