`
`
`ELSEVIER
`
`European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`Review article
`
`49.263
`
`
`
`Exrgugai
`dourDall 93
`Pirates an)
`Biowareauc
`—————
`wwwelseviercom/locate/ejphabio
`
`Improving drug solubility for oral delivery using solid dispersions
`
`Christian Leuner, Jennifer Dressman
`Johann Wolfeang Goethe University, Frankfurt am Main, Germany
`
`Received 13 December 1999; accepted in revised form 7 February 2000
`
`Abstract
`
`The solubility behaviour of drugs remains onc of the most challenging aspects in formulation deyclopment. With the advent of combi-
`natorial chemistry and high throughput screening, the number of poorly water soluble compounds has dramatically increased, Although solid
`solutions have tremendous potential for improving drug solubility, 40 years of research have resulted in only a few marketed products using
`this approach. With the introduction of new manufacturing technologies such as hot melt exirusion, it should be possible to overcome
`problems in scale-up and for this reason solid solutions are enjoying a renaissance. This article begins with an overview of the historical
`background and definitions of the various systems including eutectic mixtures, solid dispersions and solid sclutions. The remainder of the
`article is devoted to the production,the different carriers and the metheds used for the characterization of solid dispersions. © 2000 Elsevier
`Science B.V. All rights reserved,
`Keywords: Solid solution; Solid dispersion; Eutectic mixture; Amorphous state; Bioavailability; Solubility; Dissolution
`
`1. Introduction
`
`Together with the permeability, the solubility behaviour
`of a drug is a key determinant of its oral bioavailability.
`There have always been certain drugs for which solubility
`has presented a challenge to the development of a suitable
`formulation for oral administration, Examples such as
`griseofulvin, digoxin, phenytoin, sulphathiazole and chlor-
`amphenicol come immediately to mind. With the recent
`advent of high throughput screening of potential therapeutic
`agents, the number of poorly soluble drug candidates has
`risen sharply and the formulation of poorly soluble
`compounds for oral delivery now presents one of the most
`frequent and greatest challenges to formulation scientists in
`the pharmaceutical industry.
`Consideration of the modified Noyes-Whitney equation
`[1,2] provides some hints as to how the dissolution rate of
`even very poorly soluble compounds might be improved to
`minimize the limitations to oral availability:
`
`dc AMC, -C)
`dt
`hi
`
`where dC/dr is the rate of dissolution, A is the surface area
`available for dissolution, 2 is the diffusion coefficient of the
`
`* Corresponding author. Institute of Pharmaceutical Technology, Marie.
`Curie Strasse 9, 60439 Frankfurt, Germany. Tel.: +49-69-7982-9680; fax:
`+49-69-7982-9694,
`E-mail address: dressman @emuni-frankfurt.de (J. Dressman).
`
`compound, C, is the solubility of the compound in the disso-
`lution medium, C is the concentration of drug in the medium
`at time ¢ and # is the thickness of the diffusion boundary
`layer adjacent to the surface of the dissolving compound.
`The main possibilities for improving dissolution accord-
`ing to this analysis are to increase the surface area available
`for dissolution by decreasing the particle size of the solid
`compound and/or by optimizing the wetting characteristics
`of the compound surface, 10 decrease the boundary layer
`thickness,
`to ensure sink conditions for dissolution and,
`last but definitely not least, 10 improve the apparent solubi-
`lity of the drug under physiologically relevant conditions.
`Of these possibilities, changes in the hydrodynamics are
`difficult to invoke in vivo and the maintenance of sink
`
`conditions will depend on how permeable the gastrointest-
`inal mucosais to the compound as well as on the composi-
`tion and volume of the lumenal fluids, Although some
`research effort has been directed towards permeability
`enhancement using appropriate excipients, results to date
`have not been particularly encouraging. Administration of
`the drug in the fed state may be an oplion Lo improve the
`dissolution rate and also to increase the time available for
`
`dissolution; the likely magnitude of the food effect can be
`forecasted from dissolution tests in biorelevant media [3].
`However,
`the most attractive option for increasing the
`release rate is improvement of the solubility through formu-
`lation approaches.
`Table 1 summarizes the various formulation and chemi-
`
`0939-641 /OU/$ - see front matter © 2000 Elsevier Science B.¥. All rights reserved.
`PI: $0939-6411(00)00076-X
`
`Hopewell EX1070
`Hopewell v. Merck
`IPR2023-00481
`
`Hopewell EX1070
`Hopewell v. Merck
`IPR2023-00481
`
`1
`
`

`

`48
`
`C. Leuner, J. Dressman / European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`Table 1
`Approaches to improve the solubility or to increase the available surface
`area for dissolution
`
`i. Physical modifications
`Particle size
`Micronization
`
`Nanosuspensions
`Modifications of the crystal habit
`Polymorphs
`Pseudopolymorphs (including sclvates)
`Complexation/solubilization
`Use of surfactants
`Use of cyclodeatrines
`Drug dispersion in carriers
`Eutectic mixtures
`Scelid dispersions (non-molecular)
`Solid solutions
`
`if, Chemical modification
`Soluble prodrugs
`Salts
`
`cal approaches that can be taken to improve the solubility or
`to increase the available surface area for dissolution.
`Of the physical approaches, review articles have already
`been published on the use of polymorphs[4], the amorphous
`form of the drug [5] and complexation [6,7]. Decreasing the
`particle size of the compound by milling the drug powder
`theoretically results im an increase in the available area for
`dissolution, but in some cases the micronized powder tends
`to agglomerate, thereby al least partly negaling the milling
`procedure. Presenting the compound as a molecular disper-
`sion combines the benefits of a local increase in the selubi-
`
`lity within the solid solution) and maximizing the surface
`area of the compound that comes in contact with the disso-
`lution medium as the carrier dissolves. This review is there-
`fore devoted to a discussion of the use of molecular and
`near-molecular dispersions for the optimization of oral
`delivery of poorly soluble drugs.
`
`2. Definitions
`
`2,4, Simple eutectic mixtures
`
`No review of solid dispersions would be complete with-
`oul a brief descriplion of eutectic mixtures, which are the
`cornerstone of this approach to improving bioavailability of
`poorly soluble compounds. A simple eutectic mixture
`consists of two compounds which are completely miscible
`in the liquid state but only to a very limited extent in the
`solid state (Fig. 1). When a mixture of A and B with compo-
`sition 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 compoundsin 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 [9,10]. The large surface area of the resulling suspen-
`sion should result
`in an enhanced dissolution rate and
`thereby improved bioavailability.
`
`2.2. Solid solutions
`
`Solid solutions are comparable to liquid solutions,
`consisting of just one phase irrespective of the number of
`components. Solid solutions of a poorly water soluble drug
`dissolved in a carrier with relatively good aqueous solubility
`are of particular interest as a means of improving oral bioa-
`vailability. In the case of solid solutions, the drug’s particle
`size has been reduced to its absolute minimum viz.
`the
`
`molecular dimensions [11] and the dissolution rate is deter-
`mined by the dissolution rate of the carrier. By judicious
`selection of a carrier, the dissolution rate of the drug can be
`increased by up to several orders of magnitude.
`Solid solutions can be classified according to two meth-
`ods. First, they can be classified according to their misci-
`bility (continuous versus discontinuous solid solutions) or
`second, according to the way in which the solvate molecules
`are distributed in the solvendum (substitutional, interstitial
`or amorphous).
`
`2.2.1. Continuous and discontinuous solid solutions
`2.2.1.1. 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 compo-
`nents. Solid solutions of this type have not been reported
`in the pharmaceutical literature to date,
`
`2.2.1.2. 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
`
`Liquid Solution
`
`Solid A + Liquid Solution
`
`Liquid Solution
`
`Solid A +'Solid B
`
`I
`
`E
`
`B (100 %)
`
`A (100 %)
`
`Fig. 1, Phase diagram for a eutectic system (reproduced with modifications
`from Ret. [8]}.
`
`2
`
`

`

`C. Leuner, J. Dressiman / European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`Liquid Solution
`
`49
`
`
`
`
`Liquid Solution
`
`at
`
`A (100 %)
`
`B (100 %)
`
`Fig. 2. Phase diagram for a discontinuous solid solution (reproduced with
`modifications from Ref. [8]}.
`
`Fig. 3. Substitutional crystalline scelid solution (reproduced with modifica-
`tions from Ref. [13]).
`
`phase diagram is shown in Fig. 2. « and B 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 et al.
`[11]
`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.
`
`2.2.2. Substitutional crystalline, interstitial crystalline and
`amorphous solid solutions
`2.2.2.1. 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 fit into the interstices between the
`solvent molecules. A substitutional crystalline solid disper-
`sion 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 [12].
`
`2.2.2.2. 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 and 5}. As
`in the case of
`substitutional
`crystalline
`solid solutions,
`the relative
`molecular size is a crucial criterion for classifymg 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 diameter [14]. Furthermore,
`the volumeof the solute molecules should be less than 20%
`of the solvent.
`
`2.2.2.3. Amorphous solid solutions In an amorphous solid
`solution, the solute molecules are dispersed molecularly but
`irregularly within the amorphous solvent (Fig. 6}. Using
`priseofulvin in citric acid, Chiou and Riegelman [16] were
`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 amor-
`phoussolid solutions as the polymeritself 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.
`
`
`
`Pig. 4, Interstitial crystalline solid solution (reproduced with modifications
`from Ref. [13].
`
`3
`
`

`

`50
`
`C. Leuner, J. Dressman / European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`drug is molecularly dispersed in the dissolution medium,i.e.
`is present in solution form, A further reason for the improve-
`ment in the dissolution rate is that the drug has no crystal
`structure in the solid solution [22]. Therefore, the energy
`normally required to break up the crystalline structure of the
`drug before it can dissolve is not a limitation to the release
`of the drug from a solid solution. After the solid solution has
`dissolved, the dnig is present as a supersaturated solution. In
`some cases, the carrier may serve to inhibit precipitation of
`the drug from the supersaturated solution [23-25]. It has
`also been speculated that, if the drug does precipitate, it
`will precipitate cut as a metastable polymorph with a high
`solubility compared to that of the most stable form [24,26].
`A further way im which a solid solution could enhance disso-
`lution is through improvement of the wettability of the drug
`[13]. Even carriers that are not surface active, e.g. urea and
`citric acid, can improve wetting characteristics. Of course,if
`carriers with surface activity such as cholic acid, bile salts
`[27], cholesterol esters [28] and lecithin [29] are used, the
`improvements in wetting can be much greater. Another way
`in which the carrier can influence the drug's dissolution
`properties is via direct solubilization or a cosolvent effect.
`The relationship between the release characteristics of the
`solid solution and a physical mixture of the two components
`varies with the drug/carrier combination. For example, the
`release rate from a solid solution of prednisolone in Cremo-
`phore® is almost
`identical with the release rate from a
`simple mixture of the two components [30]. A physical
`mixture of glyburide and PEG 6000 exhibited better solu-
`bility and faster dissolution than that of the pure drug [31].
`The solubility of paracetamol is greater in urea than alone
`[10]. However, the solubility of sulfathiazole is adversely
`affected by mixing with urea [9]. In general, dissolution
`rates are compared among the pure drug, a physical mixture
`and the solid solution to assess the benefits of preparing a
`solid solution.
`
`3.1. Methods for preparing solid solutions
`
`3.12. Hot melt method
`
`Sekiguchi and Obi [9] used a hot melt method to prepare
`simple eutectic mixtures. Sulphathiazole and urea were
`melted together at a temperature above the eutectic point
`and then cooled in an ice bath. The resultant solid eutectic
`
`was then milled to reduce the particle size. Cooling leads to
`supersaturation, but due to solidification the dispersed drug
`becomes trapped within the carrier matrix. Whether or not a
`molecular dispersion can be achieved depends on the degree
`of supersaturation and rate of cooling attained in the
`process. In other words, the process has an effect on the
`resultant dispersion and can be varied to optimize the
`product, Sekiguchi et al. [17] and Chiou and Riegelman
`(16] accelerated the cooling rate by snap-cooling on stain-
`less steel plates. Kanig [19]
`introduced the variation of
`spraying the hot melt onto a cold surface. A further
`
`A ©
`
`Oo
`9d 0
`
`o
`
`O°
`
`©
`
`a
`
`Fig. 5, Interstitial solid selutions of small molecules in the crystalline parts
`of a polymer(reproduced with modifications from Ref. [15]).
`
`3. Formulation of solid solutions
`
`In the early 1960s, Sekiguchi et al. reported that formula-
`tion of eutectic mixtures could lead to an improvement in
`the release rate and thereby the bioavailability of poorly
`soluble drugs. Eutectic combinations such as sulphathia-
`zolefurea [9] and chloramphenicol/urea [17]
`served as
`examples for the preparation of a poorly soluble drug in a
`highly water soluble carrier, Both preparations exhibited
`faster release and better bioavailability than conventional
`formulations. The explanation offered for this behaviour
`was that, after dissolution of the urea, a fine suspension of
`drug particles was exposed to the dissolution medium (or GI
`fluids) and that both the smaller particle size and better
`wettability of the drug particles in this suspension contrib-
`uted to a faster dissolution rate.
`The next development was the preparation of solid solu-
`tions by Levy [18] and Kanig [19]. In contrast to a eutectic
`mixture,
`the dispersed component in a solid solution is
`molecularly dispersed, In a very informative series of publi-
`cations, Goldberg [10,11,20,21] discussed the theoretical
`and practical advantages of solid solutions over eutectic
`mixtures. The improvement in dissolution characteristics
`was al first attributed 100% to the reduction in particle
`size. Molecular dispersion represents the ultimate in particle
`size reduction [21], and after the carrier has dissolved, the
`
`
`
`Fig. 6. Amorphous solid solution (reproduced with modifications from Ref,
`[15).
`
`4
`
`

`

`C. Leuner, J. Dressiman / European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`3]
`
`approach is to prepare the solid dispersion by injection
`molding, as demonstrated by Wackeret al. [32].
`An important prerequisite to the manufacture of solid
`solutions by the hot melt method is the miscibility of the
`drug and the carrier in the molten form. When there are
`miscibility gaps in the phase diagram, this usually leads to
`a product that is not molecularly dispersed. Another impor-
`tant limitation to the hot melt methodis the thermostability
`of the drug and the carrier. If too high a temperature is
`required, the drug may decompose or evaporate. Of course,
`oxidative reactions can be avoided by processing in an inert
`atmosphere or under vacuum, while evaporation can be
`avoided by processing in a closed system.
`Because of
`these limitations,
`the solvent method
`became more popular in the 1970s and 1980s. In recent
`years, however, the hot melt method has enjoyed a renais-
`sance in the form of hot melt extrusion. Extrusion of
`moistened powders has been well known in the pharma-
`ceutical sciences for many years [33]. Hot melt extrusion
`is a very common way of processing plastics in the poly-
`mer industry, but Speiser [34,35] and Hiittenrach [36]
`were the first
`to adapt
`the process for pharmaceutical
`purposes. In recent years, this method has been applied
`to the manufacture of solid solutions, A scheme of a hot
`melt extruder is shown in Fig, 7, The drug/carrier mix is
`typically processed with a twin-screw extruder of the
`same type used in the polymer industry. 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 advan-
`tage 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
`thermolabile to be processed.
`A further
`alternative
`for processing thermolabile
`substances is by hot-spin-melting. Here, the drug and carrier
`are melted together over an extremely short time in a high
`speed mixer and, in the same apparatus, dispersed in air or
`an inert gas in a cooling tower. Some drugs that have been
`processed into solid dispersions using hot-spin-melting to
`
`
`
`Fig. 7. Scheme of a hot melt extruder (reproduced with modifications from
`Ref, [37]).
`
`date include testosterone [38], progesterone [39] and dieno-
`gest [40].
`
`3.4.2. Solvent method
`
`Until the advent of the solvent method, solid solutions
`were prepared exclusively by the melting method. Tachi-
`bani and Nakumara |41] were the first to dissolve both the
`drug and the carrier in a commonsolvent and then evaporate
`the solvent under vacuum to produce a solid solution. This
`enabled them to produce a solid solution of the highly lipo-
`philic B-carotene in the highly water soluble carrier poly-
`vinylpyrrolidone (PVP). The evaporation method was then
`taken up by Mayersohn and Gibaldi [42]. By dissolving both
`priseofulvin and PVP in chloroform, and then evaporating
`the solvent, they were able to achieve a solid dispersion. The
`release rate of griseofulvin from the solid dispersion was
`five to 11 times higher than that of micronized drug, depend-
`ing on the drug/carrier ratio. Bates [43] introduced the term
`coprecipitates to describe solid dispersions that are manu-
`factured by the solvent evaporation method. Although the
`term coprecipitate is strictly speaking inaccurate in this
`case, il is still widely used in this sense today. Simonelli
`et al. [44] used the term coprecipilate more correctly to
`describe a solid dispersion of sulphathiazole and PVP that
`had been precipitated from a solution in sodium chloride by
`the addition of hydrochloric acid. Solid dispersions and
`solutions that are manufactured by the solvent evaporation
`method should really be called coevaporates and not copre-
`cipitates,
`An important prerequisite for the manufacture of a solid
`dispersion using the solvent methodis that both the drug and
`the carrier are sufficiently soluble in the solvent. The solvent
`can be removed by any one of a number of methods.
`Temperatures used for solvent evaporation usually lie in
`the range 23-65°C [45,46]. The solvent can also be removed
`by freeze-drying [31] or by spray-drying [47]. It must be
`remembered that when an organic solvent is to be removed,
`small variations in the conditions used can lead to quite
`large changes in product performance. Another point to
`consider is the importance of thoroughly removing all of
`the solvent, since most of the organic solvents used have
`toxicity issues,
`With the discovery of the solvent method, many of the
`problems associated with the melting method were solved,
`For example, it was then possible to form solid dispersions
`of thermolabile substances. Likewise, many polymers that
`could not be utilized for the melting method due to their
`high melting points (e.g. PVP) could be now considered as
`carrier possibilities. As a result, for many years the solvent
`method was the method of choice for polymer-based
`systems. With time, however, the ecological and subsequent
`economic problems associated with the use of organic poly-
`mers began to make solvent-based methods more and more
`problematic, For these reasons, hot melt extrusion is the
`current methed of choice for the manufacture of solid
`
`dispersions.
`
`5
`
`

`

`52
`
`C. Leuner, J. Dressman / European Journal of Pharmaceutics and Biopharnuweutics 30 {2000) 47-60
`
`3.2. Carriers
`
`3.22. Polyethylene glycol (PEG)
`32.401. General characteristics of PEGs Polyethylene
`glycols (PEG) are polymers of ethylene oxide, with a mole-
`cular weight
`(MW) usually falling in the range 200-
`300 000. For the manufacture of solid dispersions and solu-
`tions, PEGs with molecular weights of 1500-20 000 are
`usually employed. As the MW increases, so does the visc-
`osity of the PEG. At MW ofup to 600, PEGsare fluid, in the
`range 800-1500 they have a consistency that
`is best
`described as vaseline-like, from 2000 to 6000 they are
`waxy and those with MW of 20 000 and above formhard,
`brittle crystals at room temperature. Their solubility in water
`is generally good, but decreases with MW. A particular
`advantage of PEGs for the formation of solid dispersions
`is that they also have good solubility in many organic
`solvents. The melting point of the PEGs of interest lies
`under 65°C in every case (e.g.
`the m.p. of PEG 1000 is
`30-40°C, the m.p. of PEG 4000 is 50-58°C and the m.p.
`of PEG 20 000 is 60-63°C) [48]. These relatively low melt-
`ing points are advantageous for the manufacture of solid
`dispersions by the melting method. Additional attractive
`features of the PEGs include their ability to solubilize
`some compounds [31] and also to improve compound wett-
`ability. Even the dissolutionrate of a relatively soluble drug
`like aspirin can be improved by formulating it as a solid
`dispersion in PEG 6000 [49].
`
`3.2.1.2. Influence of the PEG chain length PEGs of MW
`4000-6000 are
`the most
`frequently used
`for
`the
`manufacture of solid dispersions, because in this MW
`range
`the water
`solubility
`is
`still very high, but
`hygroscopy is not a problem and the melting points are
`already over 50°C. If a PEG with too low a MW is used,
`this can lead to a product with a sticky consistency thatis
`difficult to formulate into a pharmaceutically acceptable
`product [50]. PEGs with higher MW have also been used
`with success: products containing PEG 8000 [51] and
`10 000 [52] showed enhanced dissolution rates compared
`to the pure drug.
`The importance of the carrier to performance of the solid
`dispersion was illustrated in a study of 14 different drugs
`formulated as solid dispersions in PEG 6000 [53]. In this
`study. Dubois and Ford showed that, when the drug is
`present in a low drug/carrier ratio (<2% in the case of
`phenylbutazone. up to 15% in the case of paracetamol).
`the release rate is dependent only on the carrier and not
`on the drug properties. Results with indomethacin showed
`similar behaviour. Further studies indicated that the release
`fate is inversely proportional to the chain length of the
`PEG [54]. Similar results were obtained with etoposide
`[50] and griseofulvin [16]. However, other studies revealed
`contradictory behaviour. For example, glyburide release
`from a solid dispersion in PEG 6000 was faster than
`from a similar dispersion in PEG 4000 [31]. Possible
`
`reasons for the better release from PEG 6000 are that the
`PEG 6000 was able to dissolve more of the drug than the
`PEG 4000,
`leading to a greater percentage drug in the
`molecularly dispersed form, and that the higher viscosity
`of the PEG 6000 hindered precipitation of the drug follow-
`ing dissolution of the carrier.
`A comprehensive study of phenylbutazone/PEG solid
`dispersions indicated that the release is dependent on the
`PEG MW [54]. When the percentage of drug used was low
`(0.5-2%),
`the release followed the
`rank order PEG
`1500 > 4000 > 6000 > 20 000, at percentages of 3 and 4%
`the rank order was PEG 1500 > 4000 > 20 000 > 6000 and
`ata 5% loading the order was 20 000 > 4000 > 1500 > 6000.
`Since the rank order could be clearly correlated with the crys-
`tallinity of the solid dispersion. the authors concluded thatthe
`release is dependent on the extent to which a moleculardisper-
`sion can be formed. On the other hand, contradictory results
`were obtained with chloramphenicol/PEGsolid dispersions,
`for which
`the
`rank
`order
`of
`release was
`PEG
`6000 > 4000 > 12 600 > 20-000 [55]. In yet other cases,
`the MW of the PEG had no influence at all on the release
`rate. For example, Muraet al. [56] showed that 10% disper-
`sions of naproxen in PEG 4000, 6000 and 20 000 all exhibited
`similarrelease.
`
`3.2.1.3. Influence of the drug/PEG ratio The drug/carrier
`ratio in a solid dispersion is one of the main influences on
`the performance of a solid dispersion. If the percentage of
`the drug is too high, it will form small crystals within the
`dispersion rather than remaining molecularly dispersed. On
`the other hand, if the percentage of the carrier is very high,
`this can lead to the complete absence of crystallinity of the
`drug and thereby enormous increases in the solubility and
`release rate of the drug. Lin and Cham [57] showed that
`solid dispersions of naproxen in PEG 6000 released drug
`faster when a 5 or 10% naproxen loading was used than
`when a 20, 30 or 50% loading was used. These results
`could be explained on the basis of X-ray diffraction
`results, which indicated that dispersions with low loading
`levels of naproxen were amorphous whereas those with high
`loadings were partly crystalline. However, the upper limit to
`the percentage carrier that can be employed is governed by
`the ability to subsequently formulate the solid dispersion
`into a dosage form of administrable size.
`
`3.2.1.4. Drug/PEG systenis Griseofulvinis probably the most
`studied drug with respect to dispersion in PEGs. Chiou and
`Riegelman [16] were able to achieve a noticeable increase in
`the release rate of griseofulvin from solid dispersions in PEG
`4000, 6000 and 20 000. The fruit of research with PEG/
`griseofulvin combinations is the marketed product, Gris-
`PEG. More recent studies with griseofulvin and PEGs have
`focussed on mixtures with various emulsifying agents. SjGkvist
`et al.
`[58]
`introduced small quantities of polysorbate 80,
`polyethylenedodecylether (Brij® 35). sodium dedecylsulphate
`(SLS) and dedecylamonium bromide into 10% w/w dispersions
`
`6
`
`

`

`C. Leuner, J. Dressman / European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60
`
`53
`
`of griseofulvin in PEG 3000 and by doing so were able to
`achieve substantial increases in both the rate and extent of
`dissolution. Best results were obtained with SLS. Other
`
`combination systems, such as a griseofulvin/PEG 6000/tale
`system [47] could only achieve similar results to that of the
`two-component dispersion. However, the tale system had the
`advantages of being easier to process and being less tacky.
`An increase in the release rate by formulation as a solid
`dispersion in PEG 4000 has been observed for many drugs,
`including oxazepam [59], piroxicam [60] zolpidem [61] and
`glyburide [31]. In some cases, in vivo data have verified the
`importance of the increase in release rate to the bioavail-
`ability of the drug in question. Arias et al. [62] were able to
`show that a doubling of the release rate in vitro could be
`translated inte an increase in the diuretic effect of triamter-
`
`ene in rats. A good correlation between release data from
`solid dispersions of nifedipine in PEG 6000 and the elim-
`ination of the dmg in unne was documented in human
`studies [63]. Similarly, a two-fold increase in the release
`rate of carbamazepine achieved by formulation as a solid
`dispersion in PEG 4000 and 6000 was translated into an
`increase in the bioavailability relative to a suspension of
`the drug and the marketed product. Tegretol”
`[46].
`However, even better results could be achieved with a
`hydroxypropyl-B-cyclodextrin complex. Norfloxacin/PEG
`6000 solid dispersions also produce a moderate increase in
`bioavailability [64]. Further drugs which exhibit elevated
`release rates when formulated as PEG solid dispersions
`include $1r33557, a new calcium antagonist [65], ketoprofen
`[66], oxazepam [67], nifedipine [68], phenytoin [69], urso-
`deoxycholic acid [70]. fenofibrate [71] and prednisolone
`[30].
`There have also been several studies with PEGs of higher
`MW. Perng et al. [51] achieved a ten-fold increase in the
`release rate of an experimental 5-lipoxygenase inhibitor
`with PEG 8000 using a hot melt method. Suidies of coeva-
`porates of ibuprofen with PEG 10 000, with the tale system
`and with mixoures of the two indicated that the mixture of
`
`the PEG with tale produced the best results [52].
`
`there are few
`32.15. Problems with PEGs In general,
`toxicity concerns associated with the PEGs and they are
`approved for many purposes as excipients. The low
`molecular weight PEGs do. however,
`tend to show
`slightly greater toxicity than those of higher molecular
`weight
`[48].
`In addition, a great number of drugs are
`compatible with the PEGs. A few cases have been
`observed in which the PEG proved to have stability
`problems during manufacture by the hot melt method. A
`reduction in the PEG chain length was observed for
`combinations with disulfiram, furosemide, chlorothiazide
`and chlorpropamide [53]. Another difficulty can lie in the
`subsequent formulation of the solid dispersion into an
`acceptable dosage form. If the dispersion is too soft it can
`be difficult if not impossible to manufacture a tablet dosage
`form. This is most likely to occur if a PEG with too low a
`
`MW is used or if the drug has a plasticizing effect on the
`PEG [50].
`
`3.2.2. Polyvinylpyrrolidone (PVP)
`3.2.2.4. General characteristics of PVP Polymerization of
`vinylpyrrolidone leads to polyvinylpyrrolidone (PVP) of
`molecular weights ranging from 2500 to 3 000 G00. These
`can be classified according to the K value, which is calcu-
`lated using Fikentscher’s eq