Solid Dispersions : An Overview

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Abstract:

Over the years, a variety of solubilization techniques have been studied and widely used, by many estimates up to 40 per cent of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. The various techniques are available for enhancement of solubility. Solid dispersion is one of the most promising approach for solubility enhancement. The term solid dispersion refers 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.

There are many types of solid dispersions which includes Simple eutectic mixtures, Solid solutions, Glass solutions, Amorphous precipitation in a crystalline carrier and According to the way in which the solvate molecules are distributed in the solvendum.

Different methods are also been used for preparation of solid dispersions such as Melting method, Solvent method, Melting solvent method (melt evaporation), Melt extrusion method, Lyophilisation Technique, Melt Agglomeration Process, The Use Of Surfactant, Electrospinning and Super Critical Fluid (Scf) Technology

Keywords: solubility enhancement, solid dispersions, poorly soluble drugs

Introduction

The progress in treatment of diseases has been evident within upsurge in development of new drugs. An estimated 40% of these drugs are poorly water soluble. Although most of the drugs have encouraging experimental data obtained in vitro, the in vivo results have been disappointing. The attributes include

  1. Poor absorption, rapid degradation, and lamination (peptides and protein) resulting in insufficient concentration,
  2. Drug distribution to other tissues with high drug toxicities (anticancer drugs),
  3. Poor solubility of drugs, and
  4. Fluctuations in plasma levels owing to unpredictable bioavailability.

The enhancement of oral bioavailability of such poorly water soluble drugs remains one of the most challenging aspects of drug development. The development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubalization by cosolvents, and particle size reduction.1 Studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion .2, 3 when the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. The resulting enhanced surface area produces higher dissolution rate and bioavailability of poorly water-soluble drugs. In addition, in solid dispersions, a portion of drug dissolves immediately to saturate the gastrointestinal tract fluid, and excess drug precipitates as fine colloidal particles or oily globules of submicron size. In spite of these advantages, only 2 products have been marketed since the development of this technology 4 decades ago.

The limitations of this technology have been a drawback for the commercialization of solid dispersions. The limitations include

  1. Laborious and expensive methods of preparation,
  2. Reproducibility of physicochemical characteristics,
  3. Difficulty in incorporating into formulation of dosage forms,
  4. Scale-up of manufacturing process, and
  5. Stability of the drug and vehicle.

Solid Dispersions

The term solid dispersion refers 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 (clusters) or in crystalline particles 4,5 Therefore, based on their molecular arrangement, six different types of solid dispersions can be distinguished. They are described in Table 2. Moreover, certain combinations can be encountered, i.e. in the same sample; some molecules are present in clusters while some are molecularly dispersed.

Moreover, not the preparation method but the molecular arrangement governs the properties of solid dispersions.

List of Poorly Soluble Drugs with Hydrophilic Carriers

Table no: 131

Sr. No.

Carrier

Drug

1.

Polyethylene glycol (PEG)

Griseofulvin

2.

Polyvinylpyrrolidone (PVP)

Flufenamic acid

3.

Hydroxypropylmethylcellulose (HPMC)

Albendazole, Benidipine

4.

Sorbitol

Predinisolon

5.

Urea

Ofloxacin

Categories Of Solid Dispersions:

a. Simple eutectic mixtures

b. Solid solutions

  •  
    • According to their miscibility
      1. Continuous
      2. Discontinuous solid solutions
    • According to the way in which the solvate molecules are distributed in the solvendum
      1. Substitutional crystalline solid solutions
      2. Interstitial crystalline solid solutions
      3. Amorphous solid solutions

c. Glass solutions

d. Amorphous precipitation in a crystalline carrier

Simple eutectic mixtures

When a mixture of A and B with composition E is cooled, A and B crystallize out simultaneously, whereas when other compositions are cooled, one of the components starts to crystallize out before the other. Solid eutectic mixtures are usually prepared by rapid cooling of a comelt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. When a mixture with composition E, consisting of a slightly soluble drug and an inert, highly water soluble carrier, is dissolved in an aqueous medium, the carrier will dissolve rapidly, releasing very fine crystals of the drug 6, 7. The large surface area of the resulting suspension should result in an enhanced dissolution rate and thereby improved bioavailability.

Phase diagram for a eutectic system

Fig. 1 Phase diagram for a eutectic system

Solid solutions

Continuous solid solutions:

In a continuous solid solution, the components are miscible in all proportions. Theoretically, this means that the bonding strength between the two components is stronger than the bonding strength between the molecules of each of the individual components. Solid solutions of this type have not been reported in the pharmaceutical literature to date.

Discontinuous solid solutions:

In the case of discontinuous solid solutions, the solubility of each of the components in the other component is limited. A typical phase diagram is shown in Fig. 2.   show the regions of true solid solutions. In these regions, one of the solid components is completely dissolved in the other solid component. Note that below a certain temperature, the mutual solubilities of the two components start to decrease. Due to practical considerations it has been suggested by Goldberg 8 that the term `solid solution' should only be applied when the mutual solubility of the two components exceeds 5%. Whether or not a given solid solution can be utilized as a dosage form strategy will depend not only on the mutual solubilities of the two components but also on the dose of the drug component. The upper limit for the mass of a tablet or capsule is about 1 g. Assuming that the solubility of the drug in the carrier is 5%, doses of above 50 mg would not be feasible with this strategy. Obviously, if the drug solubility in the carrier is significantly higher than 5%, larger doses can be entertained.

Phase diagram for a discontinuous solid solution

Fig. 2 Phase diagram for a discontinuous solid solution

Substitutional crystalline, interstitial crystalline and amorphous solid solutions

Substitutional crystalline solid solutions:

Classical solid solutions have a crystalline structure, in which the solute molecules can either substitute for solvent molecules in the crystal lattice or into the interstices between the solvent molecules. A substitutional crystalline solid dispersion is depicted in Fig. 3. Substitution is only possible when the size of the solute molecules differs by less than 15% or so from that of the solvent molecules 9 .

Substitutional crystalline solid solution

Fig. 3 Substitutional crystalline solid solution

Interstitial crystalline solid solutions

In interstitial solid solutions, the dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice (Figs. 4). As in the case of substitutional crystalline solid solutions, the relative molecular size is a crucial criterion for classifying the solid solution type. In the case of interstitial crystalline solid solutions, the solute molecules should have a molecular diameter that is no greater than 0.59 of the solvent molecule's molecular diameter10. Furthermore, the volume of the solute molecules should be less than 20% of the solvent.

Interstitial Crystalline Solid Solution

Fig. 4 Interstitial crystalline solid solution

Amorphous solid solutions:

 In an amorphous solid solution, the solute molecules are dispersed molecularly but irregularly within the amorphous solvent (Fig.5) Using griseofulvin in citric acid, Chiou and Riegelman11were the first to report the formation of an amorphous solid solution to improve a drug's dissolution properties. Other carriers that were used in early studies included urea and sugars such as sucrose, dextrose and galactose. More recently, organic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and various cellulose derivatives have been utilized for this purpose. Polymer carriers are particularly likely to form amorphous solid solutions as the polymer itself is often present in the form of an amorphous polymer chain network. In addition, the solute molecules may serve to plasticize the polymer, leading to a reduction in its glass transition temperature.

Amorphous solid solution

Fig. 5 Amorphous solid solution

Glass solutions and glass suspensions:

Chiou and Riegelman first introduced the concept of formation of a glass solution as

another potential modification of dosage forms in increasing drug dissolution and absorption. A glass solution is a homogenous, glassy system in which a solute dissolves in a glassy solvent. The familiar term glass however, can be used to describe either a pure chemical or a mixture of chemicals in a glassy or vitreous state. The glassy or vitreous state is usually obtained by an abrupt quenching of the melt. It is characterized by transparency and brittleness below the glass transition temperature Tg. On heating, it softens progressively and continuously without a sharp melting point. 10

Methods Of Preparation Of Solid Dispersions:

Melting method: 12

The melting or fusion method, first proposed by Sekiguchi and Obi involves the preparation of physical mixture of a drug and a water-soluble carrier and heating it directly until it melted. The melted mixture is then solidified rapidly in an ice-bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved. Appropriately this has undergone many modifications in pouring the homogenous melt in the form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or water on the opposite side of the plate. 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. Under such conditions, the solute molecule is arrested in the solvent matrix by the instantaneous solidification process. The quenching technique gives a much finer dispersion of crystallites when used for simple eutectic mixtures.

However many substances, either drugs or carriers, may decompose during the fusion process which employs high temperature. It may also cause evaporation of volatile drug or volatile carrier during the fusion process at high temperature. Some of the means to overcome these problems could be heating the physical mixture in a

sealed container or melting it under vacuum or in presence of inert gas like nitrogen to prevent oxidative degradation of drug or carrier.

Solvent method:13

In this method, the physical mixture of the drug and carrier is dissolved in a common solvent, which is evaporated until a clear, solvent free film is left. The film is further dried to constant weight.

The main advantage of the solvent method is thermal decomposition of drugs or carriers can be prevented because of the relatively low temperatures required for the evaporation of organic solvents.

However, some disadvantages are associated with this method such as

1) The higher cost of preparation.

2) The difficulty in completely removing liquid solvent.

3) The possible adverse effect of traces of the solvent on the chemical stability         

4) The selection of a common volatile solvent.

5) The difficulty of reproducing crystal form.

6) In addition, a super saturation of the solute in the solid system cannot be attained   except in a system showing highly viscous properties.

Melting solvent method (melt evaporation):12

It involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of polyethylene glycol, which is then evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The 5 –10% (w/w) of liquid compounds can be incorporated into polyethylene glycol6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion. This technique possesses unique advantages of both the fusion and solvent evaporation methods. From a practical standpoint, it is only limited to drugs with a low therapeutic dose e.g. below 50 mg.

Melt extrusion method14, 15, and 16

The drug/carrier mix is typically processed with a twin-screw extruder. The drug/carrier mix is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder. The intermediates can then be further processed into conventional tablets. An important advantage of the hot melt extrusion method is that the drug/carrier mix is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed.

Solid dispersion by this method is composed of   active ingredient and carrier, and prepare by hot-stage extrusion using a co-rotating twin-screw extruder. The concentration of drug in the dispersions is always 40% (w/w). The screw-configuration consist of two mixing zones and three transport zones distribute over the entire barrel length, the feeding rate is fix at 1 kg/h and the screw rate is set at 300 rpm. The five temperature zones are set at 100, 130, 170, 180, and 1850C from feeder to die. The extrudates are collect after cooling at ambient temperature on a conveyer belt. Samples are milled for 1 min with a laboratory-cutting mill   and sieve to exclude particles >355µm.

Amorphous solid solution

Fig. 6 Screw and kneading elements

Extrusion screw geometry

Fig. 7 Extrusion screw geometry

Lyophilisation Technique

Freeze-drying involves transfer of heat and mass to and from the product under preparation 17. This technique was proposed as an alternative technique to solvent evaporation. Lyophilisation 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.

Melt Agglomeration Process

This technique has been used to prepare SD wherein the binder acts as a carrier. In addition, SD(s) are prepared either by heating binder, drug and excipient to a 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 mixer18. A rotary processor has been shown to be alternative equipment for melt agglomeration. 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 agglomerates19. The effect of binder type, method of manufacturing and particle size are critical parameters in preparation of SD(s) by melt agglomeration. Since these parameters result in variations in dissolution rates, mechanism of agglomerate formation and growth, agglomerate size, agglomerate size distribution and densification of agglomerates. It has been investigated that the melt in procedure gives a higher dissolution rates than the spray-on procedure with PEG 3000, poloxamer 188 and gelucire 50/13 attributed to immersion mechanism of agglomerate formation and growth. In addition the melt in procedure also results in homogenous distribution of drug in agglomerate. 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 particles 20.

The use of surfactant

The utility of the surfactant systems in solubilization is well known. Adsorption of surfactant on solid surface can modify their hydrophobisity, surface charge, and other key properties that govern interfacial processes such as flocculation/dispersion, floatation, wetting, solubilization, detergency, enhanced oil recovery and corrosion inhibition. Surfactants have also been reported to cause solvation/plasticization, manifesting in reduction of melting the active pharmaceutical ingredients, glass transition temperature and the combined glass transition temperature of solid dispersions. Because of these unique properties, surfactants have attracted the attention of investigators for preparation of solid dispersions 21, 22.

Electrospinning

Electrospinning is a process in which solid fibers are produced from a polymeric fluid stream solution or melt delivered through a millimeter-scale nozzle23. This process involves the application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen. Upon increasing the electrostatic field strength up to but not exceeding a critical value, charge species accumulated on the surface of a pendant drop destabilize the hemispherical shape into a conical shape (commonly known as Taylor s cone). Beyond the critical value, a charged polymer jet is ejected from the apex of the cone (as a way of relieving the charge built-up on the surface of the pendant drop). The ejected charged jet is then carried to the collection screen via the electrostatic force. The Coulombic repulsion force is responsible for the thinning of the charged jet during its trajectory to the collection screen. The thinning down of the charged jet is limited by the viscosity increase, as the charged jet is dried 24. This technique has tremendous potential for the preparation of nanofibres and controlling the release of biomedicine, as it is simplest, the cheapest 25 this technique can be utilized for the preparation of solid dispersions in future.

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. From the very beginning of supercritical fluid particle generation research, the formation of biocompatible polymer and drug-loaded biopolymer micro-particles for pharmaceutical applications has been studied intensively by a number of researcher groups26 CFs either as solvent: rapid expansion from supercritical solution (RESS) or antisolvent: 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 substance27 the supercritical fluid antisolvent techniques, carbon dioxide is used as an antisolvent for the solute but as a solvent with respect to the organic solvent. Different acronyms were used by various authors to denote micronization processes: aerosol solvent extraction system (ASES), precipitation with a compressed fluid antisolvent (PCA), gas anti-solvent (GAS), solution enhanced dispersion by supercritical fluids (SEDS) and supercritical anti-solvent (SAS). The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing cocurrently 28 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 temperature 29 Moreover, supercritical fluids are 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) 30

References:

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2.Goldberg AH, Gibaldi M, Kanig JL.“Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. II. Experimental evaluation of eutectic mixture: urea-acetaminophen system”. J Pharm Sci. 1966;55:482-487.

3. Goldberg AH, Gibaldi M, Kanig JL. “Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. III. Experimental evaluation of griseofulvin-succinic acid solution”. J Pharm Sci. 1966;55:487-492.

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7.Goldberg A, Gibaldi M,  Kanig L, “Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures II  experimental evaluation of a eutectic mixture: urea-acetaminophen system”, J. Pharm. Sci. 1966; 55; 482-487

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About Authors:

Rahul Panditraj Ghaste, D. D. Chougule R. R. Shah, and D. S. Ghodake

Rahul Panditraj Ghaste

Rahul Panditraj Ghaste

Appasaheb Birnale college of Pharmacy, Sangli South Shivaji Nagar A/P sangli, Tal- Miraj Dist- Sangli
e-mail- rahulghaste@gmail.com

D. D. Chougule

D. D. Chougule

Mr. R. R. Shah

Mr. R. R. Shah

Mr. D. S. Ghodake

Mr. D. S. Ghodake

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Comments

Rahul Ghaste's picture

Thank you for visiting to our publication.
any coments and Queris are welcome...!!

Bramhadev Patil's picture

I HAVE SEEN YOUR ARTICLE. ITS VERY GOOD & COVERED ALL THE POINTS RELATED TO SOLID DISPERSIONS. WHICH ARTICLE WILL BE NEXT FROM YOU?

B.A.PATIL

Rahul Ghaste's picture

thanx bramhadev next article will be on FDT ..!!

leela's picture

Nice presentation

Rahul Ghaste's picture

I am very glad to recive your comments.
thnk you very much.!!

swapnil gonjari's picture

congrets , keep it up .
we want reserch article from u.

Swapnil Gonjari
M. Pharm Student
satara college of pharmacy(SCOP),
Satara

Rahul Ghaste's picture

thanx a lot swapnil

Satish Singh Kadian's picture

Excellent
satish

Rahul Ghaste's picture

thax satish

Ayyappa Garlapati's picture

you have covered all the topic nice review

ayyappa