Assessing the performance of amorphous solid dispersions

COMMENTARY Assessing the Performance of Amorphous Solid Dispersions ANN NEWMAN,1 GREGORY KNIPP,2 GEORGE ZOGRAFI3 1

Seventh Street Development Group, Lafayette, Indiana 47901

2

Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907

3

School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705

Received 24 August 2011; revised 21 November 2011; accepted 7 December 2011 Published online 27 December 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23031 ABSTRACT: The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (∼10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API–polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1355–1377, 2012 Keywords: amorphous; bioavailability; dissolution; in vitro–in vivo correlation (IVIVC); polymers; solid dispersion; solid dosage form; absorption; stabilization

INTRODUCTION In recent years, there has been an increased interest in the use of amorphous forms of active pharmaceutical ingredients (APIs) in various formulations, especially when their crystalline forms are shown to exhibit very poor aqueous solubility. This often leads to inadequate rates of dissolution and oral bioavailability.1,2 Amorphous forms tend to exhibit high levels of supersaturation in aqueous media relative to the crystal, and thus higher apparent solubility. These increases arise from the lack of a highly ordered crystal with lattice energies that must be overcome to attain adequate solubility of the crystal.

Correspondence to: Ann Newman (Telephone: +765-650-4462; Fax: +765-742-1062; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 101, 1355–1377 (2012) © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association

As amorphous forms are thermodynamically unstable relative to the crystal, we would expect a spontaneous tendency for the solid to revert back to the crystalline form. This commonly occurs during storage in the solid state at various relative humidities and temperatures,3 and when the amorphous form encounters in vitro and in vivo dissolution media,4 which in both cases negates the solubility advantage of the amorphous form. The challenge, therefore, is to inhibit crystallization over the time period of product storage and to maintain a sufficient level of supersaturation upon oral administration without crystallization. Currently, a major strategy used to obtain good physical stability, as well as enhanced dissolution and oral bioavailability, is to use amorphous solid dispersions. In these systems, the API is combined with a water-soluble polymer to produce a single-phase amorphous mixture of the API and the polymer.5

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Such miscibility appears to be essential for maintaining long-term physical stability of the amorphous API, as well as appropriate levels of supersaturation upon dissolution. A review of the literature reveals, however, that the term solid dispersion is often used more generally to describe a variety of solid mixtures of API and excipients with the intent of improving oral bioavailability, and can include mixtures of crystalline API and polymers, solid complexes of API with complexing agents such as the cyclodextrins, and API “dissolved” in solid lipid-based excipients.2 The focus for this paper will be restricted to amorphous API–polymer solid dispersions and the term amorphous solid dispersion will be used to describe these systems. The major polymers in pharmaceutical use for preparing amorphous solid dispersions are either water soluble at all pH conditions or those exhibiting the dissolution properties of enteric coating systems under more alkaline conditions. Pharmaceutical polymers used for amorphous solid dispersions include poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone/ vinyl acetate copolymer), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate/ succinate (HPMCAS), hydroxypropylmethyl cellulose phthalate (HPMCP), and the acrylic acid-based enteric Eudragit systems. Amorphous dispersions typically are formed by combining the API and polymer in a melt extruder, or by dissolving them in a solvent, followed by drying such as in spray drying or lyophilization.6,7 The solid dispersion may contain surfactants, such as Tween 80, Span 80, Vitamin E polyethylene glycol 1000 succinate (D-"-tocopheryl polyethylene glycol 1000 succinate), or Cremophor [Polyoxyl 35 castor oil, United States Pharmacopeia (USP)/National Formulary], to facilitate processing and/or to facilitate dissolution. For example, surfactants appear to be particularly useful for facilitating the formation of amorphous dispersions during the melt extrusion process and for promoting dissolution from dispersions containing high levels of hydrophobic API. The resulting dispersion generally is considered miscible when only one glass transition temperature, Tg , is observed using differential scanning calorimetry,8,9 and when phase separation is not detectable by other analytical techniques such as X-ray diffraction9 and solid-state nuclear magnetic resonance.10 In most pharmaceutical situations, these singlephase amorphous dispersions contain amounts of API in excess of the equilibrium solubility of the API crystals in the polymer; in other words, an amount of API that is supersaturated relative to the solubility of the crystalline form. This supersaturation is maintained by the apparent miscibility of the components in the amorphous state, but often with a thermodynamic tendency for phase separation into two JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

amorphous phases and eventual API crystallization. True miscibility of amorphous components would represent a thermodynamically stable one-phase system as with the miscibility of two liquids. Recent studies have reported values for the true equilibrium solubility of selected crystalline APIs in polymers to help ascertain the maximum API load in the dispersion that would not have any thermodynamic tendency to crystallize.11,12 These values are generally quite low at temperatures near and below the Tg , which, of course, limits the amount of API (i.e., the dose) that can be produced as a true thermodynamically stable dispersion. Hence, in the case of dosage levels generally required, there is a need to use supersaturated single-phase dispersions. It should be mentioned in this regard that differences between processing conditions and handling and storage conditions may cause a supersaturated one-phase system to undergo phase separation. For example, a one-phase system formed at high temperatures, as in a melt extruder, might phase separate when cooled to lower temperatures. In such a case, the distribution of phase-separated components may or may not be homogeneous. Indeed, it is possible that even one-phase systems upon processing may exhibit clustering or other forms of inhomogeneity. In general, relatively small amounts of polymer in various dispersions have been shown to significantly inhibit crystallization both in the solid state before administration and after introduction of the dispersion into dissolution media and gastrointestinal (GI) tract fluids.4,13,14 The ability of polymers to inhibit crystallization in stored samples can be linked to the Tg of the polymer relative to that of the API and the ability of the polymer to raise the overall Tg of the dispersion, which reduces API molecular mobility at normally encountered storage temperatures and relative humidities.3,8 Polymers capable of specifically interacting with the API in the dispersion, such as through hydrogen bonding, have been demonstrated to inhibit crystallization at very low concentrations. In these systems, the effects on Tg are not significant, and the hydrogen bonding provides stability by directly interfering with the nucleation and crystal growth processes, where stronger interaction energies provide greater resistance to crystallization.13–15 The various factors that can influence the extent and rate of crystal nucleation and growth of amorphous API are quite complex, making it difficult to predict long-term stability as a function of temperature and relative humidity from studies conducted under accelerated conditions. However, it has been suggested that as a “rule of thumb” one can avoid crystallization of amorphous API over long periods by storing samples at temperatures that are in the range of 50 K or greater below the Tg of the dispersion. Such storage temperatures below Tg appear to be where the DOI 10.1002/jps

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molecular mobility of the API has been reduced to timescales of a few years.15 Once the solid dispersion encounters in vitro or in vivo dissolution media, supersaturation in solution must be maintained over a period of time that will ensure complete dissolution and potentially increase bioavailability.2,4,16 If the API and polymer dissolve rapidly, supersaturation must be maintained by factors, including the dissolved polymer, that can inhibit solution-mediated nucleation and crystalline growth of the API. In this regard, the ability of some polymers in solution to prevent crystallization of a supersaturated API solution has been demonstrated.17 It is also possible that the API–polymer combination does not dissolve immediately, but rather remains intact as a more slowly dissolving structure, thus reducing the level of API supersaturation and tendency to crystallize. It is also very likely that in such situations any surfactants present can further prevent crystallization by promoting the formation of micelles and other colloidal aggregates that interfere with solution-mediated crystallization. It has been shown, for example, that since the chemical structure of HPMCAS appears to have the characteristics of an amphiphilic- or surfactant-like polymer, hydrophobic drugs likely can interact with HPMCAS to form colloidal structures in aqueous solution, and that this mechanism may be responsible for the excellent ability of this polymer to maintain high levels of API supersaturation.16 Bile salt micelles and other lipids found in vivo in the GI tract may also function in this manner to maintain high levels of supersaturation. In summary, it appears very likely that a very critical part of obtaining long-term supersaturation upon in vivo release is the tendency for the API in the amorphous state to remain associated as colloidal structures with the polymer, with surfactants if present in the dispersion, and with natural surfactant-like materials found in the GI tract. Consequently, in vitro studies should be conducted to assess the possible importance of this mechanism, including the use of various simulated intestinal fluids. The major challenge faced by scientists using amorphous solid dispersions, therefore, is storage stability and maintenance of postadministration supersaturation. Preparation of acceptable dispersion systems includes rationally choosing methods of preparation, the best polymer and polymer molecular weight grade, the optimal API loading (or polymer concentration), and analytical and formulation methodologies that can predict and alleviate any instabilities. Once this is determined, performance of the dispersion then needs to be evaluated. This Commentary will discuss the issues associated with establishing and characterizing stable amorphous solid dispersion systems that will ultimately increase the ability of investigators to provide a cliniDOI 10.1002/jps

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cally reproducible, safe, and efficacious response upon administration. In particular, the paper will address a specific set of questions related to assessing clinical performance including: (1) Is there sufficient experimental evidence to say that amorphous dispersions always improve performance, such as bioavailability? (2) Has it been possible to demonstrate an in vitro– in vivo relationship (IVIVR) with amorphous dispersions through the use of appropriate dissolution methodology? (3) What in vivo issues should be considered when setting up animal/human studies for proof of concept and potential clinical support with amorphous dispersions?

EXPERIMENTAL EVIDENCE FOR AMORPHOUS SOLID DISPERSION PERFORMANCE Many of the papers on amorphous solid dispersions state that dispersions can help improve clinical performance (bioavailability, and in some cases bioactivity) because of the increased solubility exhibited by the amorphous drug. However, there is still a need to demonstrate the validity of this assumption in practice. A reasonable way to approach such a question is to critically evaluate the numerous published studies performed to date, determine the number of studies that have demonstrated improved performance for an amorphous dispersion, and critically assess and discuss key determining factors. It is important to define the relationship between bioavailability and bioactivity for a pharmaceutical system. Bioavailability in practice refers to the rate and extent of absorption into the blood/plasma from a dosage form and is related to pharmacokinetics (PK). Bioactivity is due to the API molecular structure and the interactions that occur with a biological target or targets to give a pharmacological response. Generally, bioactivity changes arising from an amorphous solid dispersion are related to the minimum effective and minimum toxic blood/plasma concentrations that define the Therapeutic window.18 In practice, an amorphous dispersion may increase bioactivity through the subsequent increase in the exposure level (bioavailability). In a significant number of cases, an increase in bioactivity observed for an amorphous dispersion may be the result of targeted bioavailability,19 where the concentration of the API is increased primarily in the area of the therapeutic target due to the increased exposure. Therefore, the increase in exposure can influence the pharmacodynamics (PD) observations made but does not alter the API’s bioactivity. To assess the question of improved bioavailability for amorphous solid dispersions, a reasonably JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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significant sample of research papers were collected where bioavailability, or exposure, of amorphous solid dispersions was reported. An attempt was made to include as many studies as possible to get representative data, although it is acknowledged that the resulting list cannot be considered comprehensive. Over 80 papers were found that included the use of solid dispersions in animal or human studies. The reports were reviewed to determine if sufficient characterization data were available to confirm that the drug was amorphous. If the drug was amorphous, the excipients in the studies were then evaluated and studies with polymers as the main component were included. Ternary systems with a polymer and a surfactant or lipid were also included if the polymer was the main component. Systems containing the API dispersed only in surfactants and lipid formulation components, R and phospholipids, were not insuch as Gelucire cluded because they were considered lipid-based systems that rely on a different supersaturation mechanism, for example, micelles and microemulsions. Cyclodextrin-based systems were also not included in our analysis because complexation is the predominate mechanism used to produce a supersaturated system. On the basis of these criteria, a total of 40 studies were surveyed, as summarized in, Table 1.20–69 For the first assessment, results from the biological studies were broadly placed into three categories: (1) the amorphous dispersion improved the bioavailability, (2) the amorphous dispersion bioavailability was lower than that of a reference entity, and (3) the amorphous dispersion demonstrated the same bioavailability as the reference entity. In some cases, the amorphous dispersion was compared with more than one reference entity; if the amorphous dispersion showed better performance than one entity but not all, it was placed in category 1 (improves performance). On the basis of these criteria, we can conclude that the use of an amorphous dispersion produced improved bioavailability in 82% of the cases (33 reports). The amorphous dispersion exhibited poorer bioavailability in approximately 8% of the cases (three reports), and the same bioavailability was reported in nearly 10% of the cases (four reports). These data suggest that in the majority of reported cases, an amorphous dispersion did improve the performance of a poorly soluble API. However, there is the possibility that studies showing negative results were not reported and internal unreported results may be different. The first assessment discussed above did not take into consideration the reference materials used for comparison with the amorphous dispersion. A variety of reference entities were reported including crystalline material, physical mixtures of polymer and crystalline drug, simple capsule or tablet formulations, oral solutions or suspensions, and marJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

keted products (beads, capsules, tablets, and suspensions). The majority of studies compared the amorphous solid dispersion with the crystalline material (49%). Marketed products (26%), solutions (7%), and other dosage forms (9%) were also used. Amorphous dispersions increased bioavailability approximately two to 82 times over the respective crystalline materials when an improvement was obtained and up to seven times when compared with marketed products. The appropriate material used for comparison obviously will vary depending on the stage of development, properties of the API, and available alternatives. For many poorly soluble early development candidates, comparison of the amorphous solid dispersion to the crystalline material in a small bioavailability study can give valuable information on whether to move a compound forward. For marketed products, an amorphous dispersion may be part of the life cycle management of the drug by making a modified drug product with improved performance and a simplified formulation. This can be accomplished by adding other benefits such as a reduction in the number of doses, which results in increased patient compliance. For these later stage studies, comparison with the marketed product is more applicable. It is interesting to note that the formulations used for crystalline reference materials also varied. Neat crystalline drug in a capsule was used in 62% of the studies and 14% of the studies used a formulation containing excipients. Another common option was a suspension of the powder, which was used for both the crystalline material and the amorphous solid dispersions in 24% of the studies. None of the suspension studies reported the amount of drug dissolved in the suspension vehicle, which may be significantly different for crystalline and amorphous materials. For instance, varying amounts of drug in solution could significantly impact the bioavailability or alter the potential nucleation and formation of crystalline material from an amorphous form. It is recommended that if suspension formulations are used, the amount of drug dissolved should be determined. Several other factors during storage or use may also significantly affect the net bioavailability of a suspension including solution stability, buffer capacity, and interfacial phenomena occurring in the suspension, and should also be investigated for amorphous solid dispersions. These factors related to the dosing of a suspension require careful consideration when preparing a protocol for an in vivo pharmacokinetic study.

IN VITRO–IN VIVO PREDICTABILITY Overview Although it is acknowledged that other types of in vitro testing are necessary for development, such as permeability testing with cell cultures, dissolution DOI 10.1002/jps

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Table 1.

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List of Amorphous Solid Dispersions Evaluated for In Vitro–In Vivo Performance

Study

Drug

Polymers

Species

1 2 3 4 5

Albendazole Albendazole AMG 517 Compound 1 Compound 1

PVP HPMC, HPMCP HPMCAS. HPMC Gelucire, PEG/polysorbate 80 PVP

Rabbit Rabbit Monkey Dog Dog

6 7 8 9 10 11 12 13 14

Cyclosporine A ER-34122 Esomeprazole Zn Fenofibrate Frusemide (furosemide) Halofantrine Hoffman-La Roche drug Indomethacin Indomethacin

Polyoxyethylene stearate (S40) HPMC PEG PVP Eudragit PVP PEG, gelucire, TPGS PVP, polaxamer HPC, HPMC, HEC PEG, HPMCP

Rat Dog Human Dog Human Dog Dog Human Rabbit

15

Indomethacin

PEG

Rabbit

16 17 18 19 20 21 22 23 24 25

Itraconazole Itraconazole Itraconazole Itraconazole Itraconazole Itraconazole Ketoconazole KRN633 Lonidamine MFB-1041

HPMC CAP, PVAP HPMCP PEG HPMC Eudragit, PVP/VA PEG PVP PEG, PVP HPMC, HPMCP, CMEC

Rat Rat Dog Human Rat Human Rat Rat Rat Dog

26 27 28 29 30 31

Nifedipine Nifedipine Nifedipine Nifedipine Nifedipine Nimodipine

PEG, phosphatidylcholine PEG, PEG MME PVP PVP PVP HPMC, PVP/VA, Eudragit

Rat Rabbit Dog Dog Dog Dog

32 33

Nitrendipine Pranlukast

HPMCP, Eudragit, EC Gelatin

Dog Rat

34 35 36 37 38 39 40

R103757 Ritonavir Ritonavir and lopinavir RP69698 Tacrolimus Tolbutamide Tolbutamide

HPMC PEG Dopovidone, sorbitan monolaurate PEG PEG, PVP, HPMC PEG PVP

Dog/human Dog Human Dog Dog Rabbit Dog

Dissolution Media

IVIVR

Reference

NA Phosphate buffer (pH 6.8) Phosphate buffer (pH 6.8) 0.05 N HCl pH 2 buffer (0.1 N HCl), pH 6.8 with 0.1% SLS Water Phosphate buffer (pH 6.8) Phosphate buffer (pH 6.8) 0.1 M HCl (0.36% SDS) SGF without enzymes, SIF 0.1 N HCl, water SGF without enzymes Water (around pH 7) Phosphate buffer (pH 7.2), NaCl Phosphate buffer (pH 7.2), NaCl 0.1 N HCl 0.1 N HCl, (pH 6.8) NA SGF without enzymes, SIF SGF without enzymes SGF without enzymes SIF without enzymes SGF Water Phosphate buffer (pH 1.2 and 6.8) Water SGF Water Water Water with 0.1% HCO-60 Acetate buffer (pH 4.5) with 0.05% SDS Water (with 0.5% SDS) Phosphate buffer (pH 3, 5, and 7) 0.1 N HCl 0.1 N HCl NA Water pH 1.2 pH 2 buffer Phosphate buffer (pH 6.8)

NA Y Y Y Y

20,21 22 23 24 25

NA Y Y NA Y Y N Y Y

26 27 28 29 30–32 33 34 35 36

N

37

Y N NA Y NA N Y Y Y Y

38 39 40 41 42,43 44–47 48 49 50 51

NA N Y Y Y Y

52 53 54 55 56 57,58

Y Y

59 60

N Y NA NA Y N Y

61 62,63 64 65 66 67,68 69

CAP, cellulose acetate phthalate; CMEC, carboxymethylethylcellulose; EC, ethyl cellulose; HEC, hydroxyethyl cellulose; HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; HPMCAS, hydroxypropyl methylcellulose acetate succinate; HPMCP, hydroxypropyl methylcellulose phthalate; PEG, polyethylene glycol; PEG MME, polyethylene glycol monomethyl ether; PVAP, polyvinyl acetate phthalate; PVP, polyvinyl pyrrolidone; PVP/VA, polyvinyl pyrrolidone vinylacetate; TPGS, D-"-tocopheryl polyethylene glycol 1000 succinate; NA, not available; HCl, hydrochloric acid; SIF, simulated intestinal fluid; SGF, simulated gastric fluid; NaCl, sodium chloride; SLS, sodium lauryl sulfate; SDS, sodium dodecyl sulfate; HCO-60, surfactant.

testing will be the primary in vitro method discussed in this Commentary based on the large amount of literature directly related to dissolution of amorphous solid dispersions. One reason for collecting in vitro dissolution data for amorphous solid dispersions is to try to predict the in vivo biological performance. There are two types of predictions for in vitro and in vivo data known as (IVIVRs) and in vitro–in vivo correlations (IVIVCs).70 IVIVR is a broad term that includes qualiDOI 10.1002/jps

tative and semiquantitative associations between the data. IVIVC, on the contrary, is a predictive mathematical model that requires an evaluation of predictability and degree of validation as outlined by the US Food and Drug Administration (FDA).71,72 IVIVC can also be related to the Biopharmaceutics Classification System (BCS) classification of the drug.73 For Class II drugs, IVIVC can be expected if the in vitro dissolution rate is similar to the in vivo dissolution rate. In early development, IVIVR is the likely JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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method used to compare dissolution data and early animal studies. These studies, particularly for BCS Class II and IV compounds, can be extremely valuable in moving the drug development process forward with a minimum of in vivo work. For both Class I and Class III compounds, the achievement of an IVIVR/IVIVC is more related to physiological factors including gastric emptying rates and permeability, respectively. In many cases, dissolution methods are revisited after biological data are available and modified to provide the IVIVR/IVIVC.70 Of the 40 studies discussed above, 32 papers included details on dissolution studies and these data were used to determine a qualitative IVIVR. In 78% of these cases, there was a relationship between the dissolution and bioavailability data; the other 22% did not show an IVIVR. Therefore, it appears that it would be useful to more closely examine factors that are important in the dissolution and absorption processes used in these types of studies. Factors involved in in vitro testing that might have influenced results in the studies reviewed will be discussed first, followed by factors related to the in vivo conditions.

Table 2. Number of Studies Utilizing Different Particle Size Ranges of Amorphous Solid Dispersions Reported Particle Size (:m) 7–10 45–250 90–150 90–250 <115 <125 <149 149–250 149–420 <150 150–250 <177 <180 <250 250–420 280–900 <300 <355 <425 <500 850–1700

No. of Studies 1 1 1 1 1 1 3 2 1 2 1 1 1 2a 1 1 1 1 1 1 1

Italics represents particle sizes where no IVIVR was obtained. a Only one of the two studies using a particle size <250 showed no IVIVR.

In Vitro Factors To begin any analysis of dissolution data, it is important to consider the intrinsic properties of the solid API and the particles making up the formulation. As expected, particle size clearly has been shown to affect dissolution results as shown with a study with the API, nitrendipine.74 Different particle sizes of the amorphous solid dispersions (200 nm, 620 nm, 2.7 :m, 4.1 :m, 20.2 :m) resulted in large differences in the dissolution rates in fasted state simulated intestinal fluid (FaSSIF), which translated to significantly different bioavailability values (61.4%, 51.5%, 29.4%, 26.7%, and 24.7%, respectively) in rats. In our survey, the role of particle size was reported and evaluated in 26 studies. In these cases, the materials were sieved before being used for dissolution experiments or animal studies, and a wide range of particle sizes were observed (7–10 to 850–1700 :m), as shown in Table 2. Studies that did not show an IVIVR reported a variety of particle sizes, including 90–150 :m,53 <250 :m,61 <355 :m,42,43 <425 :m,34 and 850–1700 :m.69 Although these data mostly fall on the high end of the particle size range, there does not appear to be a direct relationship between particle size and the lack of IVIVR. It is not clear if the differences in predictability arise from uneven surfaces created during the dissolution of amorphous dispersions, dissolution media differences, physiological confounders, or other unknown factor(s). A suggestion for some amorphous solid dispersion systems would include a more discriminatory study with different particle size ranges versus dissolution or JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

bioavailability to develop stronger relationships or correlations. The role of different dissolution media and/or the differences in the physicochemical properties of the compounds could also be contributing factors.75–77 When a dissolution method is first being developed, the purpose of the method needs to be established. In most cases, a quality control (QC) method to differentiate drug product properties is the ultimate goal. However, in early development, the goal may be to predict the performance in a biological system when animal data are not available. Although a single dissolution test method for IVIVR/IVIVC and QC purposes would be ideal, this may not be possible for many systems. In many cases, IVIVR/IVIVC test methods would not be practical for QC testing because the extent of dissolution is too low or because the method is too complicated for routine testing. A recent study highlighted the fact that refinement of early screening tools used to predict clinical outcomes, such as dissolution testing, would have a significant impact on reducing later stage attrition.78 For this reason, it is important that dissolution methods continue to evolve to provide the necessary data for various stages of development. The first consideration is the choice of the type of dissolution vessel to use, as described in the USP under the general chapters of Dissolution and Drug Release.79 Apparatus 1 (basket method) and Apparatus 2 (paddle method) are the most common dissolution methods used. However, Apparatus 3 DOI 10.1002/jps

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(reciprocating cylinder) and Apparatus 4 (flowthrough cell) offer advantages for low solubility drugs by producing sink conditions and allowing controlled pH and volume changes of the dissolution media throughout the test. It has also been shown that Apparatus 3 can give similar results compared with Apparatus 2 if the right conditions are used.80 Other two phase dissolution systems have been reported that attempt to mimic the GI tract (stomach and duodenum) to give a better correlation with bioavailability studies.81–83 In one of these systems,81 the crystallization of an amorphous form during dissolution was observed and the dissolution results still compared favorably with dog bioavailability studies. In our survey, the majority of studies used Apparatus 2 (71%) as shown in Figure 1a. However, other dissolution systems were used including a specific method developed for suppository dissolution36 and smaller laboratory scale methods.69 When choosing dissolution media, it is generally recommended that dissolution experiments be performed under sink conditions. The USP defines sink conditions as three times the volume of dissolution media that is required to saturate a particular drug in that media,84 whereas the British Pharmacopeia states that sink conditions normally occur in a volume of dissolution medium that is at least five to 10 times the saturation volume.85 Although it is routine to assume sink conditions in such situations, it is recommended that for poorly soluble drugs other factors such as nonsink conditions and possible precipitation also be considered. In our survey, it is interesting to note that only 8% specified sink conditions, 6% specified nonsink conditions, and 86% did not specify the conditions used. It is not known whether the conditions were not specified because sink conditions were assumed or that it was simply not determined. Media selection is one of the first method development parameters to consider and this is where the purpose of the method needs to be established. A QC method that will look at batch to batch quality testing should be partly based on the available apparent solubility data and the dose range of the drug product required to ensure that sink conditions are met. If

Table 3. Characteristics of Regional Environments along the Human Gastrointestinal Tract86

Region Esophagus Stomach Duodenum Jejunum Ileum Colon

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Length (m)

Surface area (m2 )

pH

Residence Time

0.3 0.2 0.3 3 4 1.5

0.02 0.2 0.02 100 100 3

6.8 1.8–2.5 5–6.5 6.9 7.6 5.5–7.8

>30 sec 1–5 hr >5 min 1–2 hr 2–3 hr 15–48 hr

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Table 4. Variation in the Regional Human of Gastrointestinal Fluid Volumes in the Fasted and Fed States87

Stomach [volume (mL)]a Fasted Minimum Maximum Median Mean (SD) Fed Minimum Maximum Median Mean (SD)

Large Small intestine intestine [volume (mL)] [volume (mL)]

13 72 47 45 (18)

45 319 83 105 (72)

1 44 8 13 (12)

534 859 701 686 (9.3)

20 156 39 54 (41)

2 97 18 11(26)

a Volume of the stomach after the meal represents the filling volume (not only fluid).

the method is to be used to investigate biopharmaceutical properties, it is important that it closely simulates the environment in the GI tract rather than only produce sink conditions. Therefore, the use of biorelevant media is strongly recommended. When developing dissolution methods for amorphous solid dispersions in early development, the physiological pH range of 1.2–7.2 should generally be targeted. The dissolution medium composition, volume, and the experimental time should also be varied to gain additional information relevant to biopharmaceutical conditions (Tables 3 and 4). Another method for choosing the medium is to calculate the dose–solubility ratio.74 It is suggested that this ratio be used to help guide the selection of an optimum formulation by considering the dose to be used and the solubility in the dissolution media. A dose solubility ratio greater than 250 indicates that the GI conditions are less than favorable for drug dissolution. As an example, nitrendipine exhibits a dose solubility ratio greater than 8000 based on a 40 mg dose and a solubility of 5 :g/mL in FASSIF.74 On the basis of this ratio, it is probable that some of the solid will not dissolve instantly in the GI tract and sink conditions will not be achieved in vivo. The inability to reach sink conditions may also be affected by the relative differences in the fluid volumes that are not uniformly distributed throughout the GI tracts, particularly when comparing different patients (Table 4). The different effects of absorption and dissolution kinetics in physiological systems on sink conditions can also play a role. Various dissolution media were utilized in the reports on solid amorphous dispersions that were examined for this Commentary. As shown in Figure 1b, 13 different dissolution media were used, with pH values ranging from acidic to neutral. The most common media used were 0.1 N HCl solutions (21%) and water (18%) with simulated gastric fluid (SGF) without JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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Figure 1. Comparison of reference materials used in bioavailability studies: (a) USP apparatus and (b) dissolution media (green acidic media, blue neutral media).

enzymes and pH 6.8 solutions next in line (15% and 17%, respectively). A wide range of acidic pH values are represented; however, a large portion of the studies used dissolution media close to a neutral pH (50%), as represented by the blue bars in

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Figure 1b. The studies that did not show an IVIVR used SGF,39,44–47,53,67,68 pH 7.2 phosphate buffer,36 pH 2,36 and 0.1 N HCl.61 These studies covered a wide range of possible media and pH ranges relevant to the in vivo pH ranges found in Table 3. However, it is

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Figure 2. Comparison of dissolution parameters: (a) media volume and (b) agitation rates.

interesting to note in Table 3 that there is a significant pH range for both the stomach (pH 1.8–2.5) and intestine (pH 5–7.6), which is not typically captured during most dissolution testing. It is recommended that drug dissolution also be evaluated as to the importance of regional dependence, such as enteric-coated formulations that are largely targeted to the intestines. With these types of dosage forms, dissolution media and pH selection will be critical when developing an IVIVR/ IVIVC and these factors need to be considered early in the predictive dissolution testing design stage.87–89 A comparison of the amount of dissolution media used in these studies is given in Figure 2a. Fiftytwo percent of the studies used 900 mL and 32% used 500 mL; these are typical volumes for many dissolution studies. It was interesting that 91% of all dissolution studies were performed in 500 mL of media or greater, whereas actual GI fluid volumes tend to be considerably lower in most cases as shown in TaDOI 10.1002/jps

ble 4. Smaller volumes were also used in the studies (25 mL of solution69 ) likely due to limited materials being available, which is common in early development. For paddle and basket methods, the agitation can also play an important role, and yet speeds ranging from 25 to 200 rpm were reported in our survey, as shown in Figure 2b. The majority of studies (60%) were performed using 100 rpm with the next most common options being 50 rpm (18%) and 75 rpm (10%). Although stirring rate is an important factor in dissolution testing, it is suggested that investigations related to mixing and agitation rates encountered in vivo also be conducted.90–96

In Vivo Factors An important decision point for in vivo studies is the animal model to be used, especially in early development studies. In our survey, five species were used in the in vivo studies as shown in Figure 3. The most JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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Figure 3. Breakdown of species used in bioavailability studies using amorphous solid dispersions.

common animal used for bioavailability assessment was the dog (41%). The rat was used in 24% of the studies, with rabbits, humans, and monkeys utilized to a lesser degree. One study used dogs to initially test formulation concepts (tablet with crystalline drug, film-coated beads, oral solution) and then moved to human studies to test specific solids.61 Another study used dogs as their model but pretreated them with histamine “to reduce the gastric pH and create an environment that more closely mimics human physiology.”62,63 Rabbits with low acidity (pH < 5) were used to study the effect of pH because gastric pH was reported to have a significant effect on the absorption of albendazole.20,21 In our survey, the studies that did not show IVIVR used rats (one study), rabbits (three studies), dogs (two studies), and humans (two studies). Current drug product safety regulations mandate that the PK and PD of new chemical entities are to be tested in both rodent and nonrodent laboratory animals prior to human administration.97,98 The selection of the most appropriate nonrodent species is a complex issue that should take into account several factors including: (1) physiological (e.g., metabolism and morphology) similarities between the reference animal and the corresponding human organ, (2) predictive power of the process being modeled in the test animal relative to the analogous process in humans, and (3) cost and availability of the experimental animals. Manageability and behavior characteristics are also factors, and can include growth rate, size at maturation, reproduction rate, and interaction with humans in a laboratory environment.97 On the basis of these considerations, several different animal species are currently and extensively used as models to predict human bioavailability of various drug candidates including rodents, dogs, primates, and more recently pigs and minipigs.97,98 In order to build a more simplistic view of regional GI diversity, the gastrointestinal transit and drug absorption (GITA) model has been proposed.99 The GITA divides the GI tract into eight regions: JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

stomach, duodenum, upper jejunum, lower jejunum, upper ileum, lower ileum, cecum, and colon. The division enables one to consider only the relevant factors within these regions that need to be considered with respect to drug dissolution and absorption. When looking at the GI tract in more detail, differences in regional fluid volumes are apparent, as summarized in Table 4. In contrast to the majority of the dissolution medium volumes (500–900 mL) used in the papers being reviewed, Table 4 reveals that the fasted GI tract fluid volumes are approximately 100 mL or lower.98,87 The mean regional fluid volumes in the stomach and along the small and large intestines under the fasted state have been determined to be approximately 45, 105, and 13 mL, respectively. In the fed state, the mean regional free fluid volumes in the stomach (meal and fluid combined), the small and large intestines were observed to be approximately 686, 54, and 11 mL, respectively, which are significantly different than the fasted state.87,89 Flow rates through the small intestine (jejunum) were determined to be 0.6–1.2 or 2–4.2 mL/min in the fed and fasted states, respectively, suggesting that a difference in hydrostatic pressure also existed in vivo.100,86 Taken together, this suggests that lower dissolution volumes may more accurately reflect the in vivo dissolution process and it is recommended that smaller volumes be used when IVIVR is needed. Furthermore, churning and agitation will differ based on the fed and fasted states; therefore, a closer inspection of the dissolution apparatus speeds and a better assessment of the agitation on dissolution also needs to be considered.91–96 The presence of food will change the pH in the stomach; however, the changes are not uniform throughout the three distinct regions of the stomach (fundus, body, and antrum).101,102 It was revealed that the gastric body and fundal pHs raised to a pH 4.5 in a time-dependent manner postfeeding,101 whereas the antral pH remained at 2 throughout the time that food was present. These results may suggest that the stomach be considered as two separate regions in the fed state when utilizing the GITA model or a derivative.99,103–105 On the basis of the volume differences observed in the fed and fasted state, it is suggested that this factor be investigated in the in vivo studies. In our survey, 80% of the studies specified that a fasted state was used for the bioavailability studies. Free access to food was allowed in 7% of the cases, whereas the fed state was reported for 9% of the papers. The fasted versus fed state was not reported for 5% of the studies. For those studies using the fasted state, a variety of fasting times were reported ranging from overnight to 48 h, as shown in Figure 4a. Overnight fasting was the most common (29%), followed by 24 h (24%) and 12 h (12%). In 18% of the cases, the fasting time was not specified. DOI 10.1002/jps

ASSESSING THE PERFORMANCE OF AMORPHOUS SOLID DISPERSIONS

Figure 4. Comparison of (a) fasting times and (b) postdose feeding times.

Postdose feeding times were also evaluated and ranged from 2 to 12 h with 4 h being the most common postdose feeding time, as shown in Figure 4b. In 76% of the studies, the postdose feeding time was not specified. With respect to gastric regional pH changes, gastric residence times, and fluid volumes, the changes in prefeeding and postfeeding times may drastically affect the net in vivo dissolution.75–77,89,87,102 For example, deviations may be in part due to differences in gastric emptying rates and subsequent GI transit times that would impact the distribution of water-sensitive capsules in vivo.89 Studies have shown that the transit times of administered doses to human patients between the fed, fasted, and 45 min postdose feedings were largely influenced by gastric emptying rates. Therefore, along with volume, it is recommended that postfeeding times and gastric emptying rates be investigated because they DOI 10.1002/jps

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play a significant role in controlling the small intestinal transit times, which can affect absorption and bioavailability.100,106–108 There are several essential protocol design issues that need to be considered in conducting animal bioavailability studies. One important issue is that doses should be selected to yield physiologically relevant peak and trough levels expected or established in humans, where possible. For comparative purposes, doses administered to animals also need to be adjusted to body weights to control interspecies comparisons. For comparative purposes, doses administered to animals need to be adjusted to body weights to control interspecies comparisons. Consider the nifedipine cases evaluated in this Commentary.52–56 In the study by Law et al.,52 nifedipine was administered in a phosphatidylcholine–PEG 5000 solid dispersion that resulted in a 3.4-fold increase in the bioavailability in rats. In a separate study by Emara et al.,53 nifedipine mixed with PEG 6000 using the fusion method increased the maximum plasma concentration (Cmax ) by over 10-fold and the area under the plasma concentration versus time curve from 0 to 10 hours (AUC0→10 h ) by approximately sixfold in rabbits, although there was an apparent rapid burst in release based on the significantly shorter maximum concentration time (Tmax ). In the beagle dog model,55 it was demonstrated that the bioavailability of nifedipine in a PVP coprecipitate was significantly increased as evidenced by a fivefold change in Cmax and a threefold change in AUC0→240 min in comparison with the physical mixture. Although these studies indicate that there were changes in the relative bioavailabilities for nifedipine in each species, the resulting factors for the increases were based on several factors including methods of preparation, study protocol, species differences, and differences in analytical methodology. Two systems have been developed to relate the effect of dissolution/solubility with respect to in vitro permeability for making early, preclinical predictions about the potential clinical performance. These are the BCS109 and the expanded Biopharmaceutics Drug Disposition Classification System (BDDCS).110 The most important difference between the two systems is the incorporation of transporter and metabolism effects into the BDDCS, which should yield a more clinically relevant prediction in contrast to the BCS. The BCS and BDDCS classes for the compounds used in the survey are summarized in Table 5. A total of 28 drugs were included in the 40 studies reviewed and the class was assigned based on information in the literature. For BCS, 39% of the drugs were classified as Class II, 14% as Class 4, 4% as Class I, none as Class III, and 11% were not able to be classified based on available data. In 32% of the reports, low solubility was specified, but the permeability was not reported; these cases are listed as Class III or IV. For JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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Table 5. Classes

Summary of the Evaluated Drugs in BCS and BCDDS

Class Class I Class II Class III Class IV NA Class II or IVa

Percent in BCS Class

Percent in BCDDS Class

4 39 0 14 11 32

0 48 4 4 44 –

a Reported to be poorly soluble but no permeability data available; used only for BCS classification.

BDDCS, a higher percentage (61%) was not classified because of a lack of data. For those that were classified, 32% were found to be Class II, 4% were found to be Class III, 4% were found to be Class IV, and none were found to be Class I. In our survey, the compounds that did not show an IVIVR were mostly BCS Class II (indomethacin,37 itraconazole,39,44–47 R103757,62,63 and tolbutamide69 ) and one was Class I (nifedipine53 ). Another topic that is often not considered is the role of gender on polymer or API performance in an amorphous solid dispersion. For example, it has been demonstrated that PEG 400 can affect the bioavailability of a BCS Class III compound, ranitidine, differently in males compared with females.111 The effects of gender on metabolism and transport are fairly well established in most species. However, gender-based differences in bioavailability enhancement from specific polymers are often overlooked and should be investigated for many systems. This may be of particular importance when employing biodegradable polymers that are subject to metabolism.112

PHARMACEUTICAL CONSIDERATIONS WHEN DEVELOPING AMORPHOUS SOLID DISPERSIONS As our review of the literature shows, amorphous dispersions are a viable choice for early and late pharmaceutical development. However, it is important to recognize that there are a number of factors that should be considered when developing these materials into drug products, as listed in Table 6. This final section will highlight issues associated with physical attributes, in vitro testing, and in vivo evaluation that are believed to be important for testing and developing amorphous solid dispersions, with particular emphasis on ensuring therapeutic performance. Physical Attributes The analysis of the available literature and the appearance of recent commercial products reveal the significant practical advantages of using the amorphous form of an API. Their ability to enhance disJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

solution and oral bioavailability of a poorly soluble API can be utilized during various stages of development, ranging from early safety assessment to the marketed product. From a physical perspective, three areas must be examined: formulation and processing of dispersions, insuring physical stability during processing and storage, and assuring that sufficient levels of supersaturation are maintained after dissolution in vivo. The first level of concern is the choice of a polymer– API composition that can be conveniently processed as a solid dispersion and then formulated into either capsules or tablets. This begins with the choice of the method of processing, be it melt extrusion or spray drying.6,7 The choice of a method must be based on an understanding of the physical characteristics of the API, the polymer and the final dispersion. Particularly in the case of melt extrusion, a moderate Tg , still greater than that of the API, is desirable, and surfactants may be required as part of the dispersion to facilitate processing. During spray drying, relative solubilities of components in suitable solvents will be important to ensure homogeneous one-phase systems. The ability to form a one-phase “miscible” polymer mixture needs to be evaluated early in the process. Both thermodynamic and kinetic factors need to be optimized to prevent crystallization over the time period for handling and storage of the amorphous solid dispersion. In this regard, attention must be paid to the chemistry of the polymer, its molecular weight, the extent to which the API and polymer are actually miscible, the Tg , and level of hygroscopicity.5 Whether or not other excipients used to form the amorphous solid dispersion, such as surfactants, have a significant effect must also be considered. It is recommended that the following physical properties be evaluated for amorphous dispersions: particle size, hygroscopicity, mechanical properties, wettability, chemical stability, and the nature of the mixing of the API and excipients making up the dispersion. The possible impact on physical stability of other excipients added to the dispersion and formulation to facilitate manufacturing processes and therapeutic performance should also be evaluated. The most difficult physical factor to control is the ability of the dispersion to resist crystallization once it has encountered the dissolution media. Rapid dissolution of API in the supersaturated state certainly would appear to be an asset in obtaining good bioavailability. However, it may be equally important for the polymer to provide protection against solutionmediated crystallization by remaining in close contact with the API.17 This may be accomplished by direct inhibition in solution by the dissolved polymer, or by not immediately releasing the entire dose of API in the supersaturated state, yet still providing an adequate level of supersaturation. The challenge is not to DOI 10.1002/jps

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Table 6.

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Pharmaceutical Considerations for Developing Amorphous Solid Dispersions

Area Physical

Considerations Choice of polymer

Polymer–API ratio

Miscibility Manufacturing processes

Hygroscopicity Dissolution

Dissolution apparatus and media conditions

Sink versus nonsink conditions

Polymer controlled dissolution/wettability

Supersaturation in dissolution testing over hours Biological

Fasting- versus Fed-pH effects Sink versus nonsink conditions

Local effect of polymers on pH Species differences Transporters and metabolism Gastrointestinal physiology

have the polymer become the rate-limiting factor in a negative manner. It is suggested that these factors be tested and that the mechanisms be investigated when using amorphous solid dispersions.

In Vitro Testing Along with the routine parameters that need to be optimized for dissolution testing, other factors need to be considered when developing methods for amorphous solid dispersions. It is important that the methods be tailored to provide the desired information during development. For many studies involving amorDOI 10.1002/jps

Recommendations Polymer characteristics (solubility, melting point, wettability, hygroscopicity, effect of pH, dissolution rate, etc.) and large scale manufacturing process (spray drying and melt extrusion) need to be considered early in the development of the amorphous solid dispersion. Optimize the amount of polymer required to provide the long-term physical stability desired in the solid state and crystallization inhibition in solution. Determine if a one-phase miscible system has been produced. Consider that the amorphous solid dispersion produced at elevated temperatures may be miscible but may separate upon cooling to room temperature or under other conditions. Water uptake and the effect on Tg , physical stability, and crystallization need to be evaluated. Dissolution method development should focus on conditions that mimic the GI tract (biorelevant media that match the delivery route, pH, stirring rate, and volume); these conditions may not be applicable for routine dissolution testing to discriminate differences between lots. Both sink and nonsink conditions should be investigated and compared with data from the in vivo studies; for poorly soluble drugs, nonsink conditions and the possibility of crystallization in the GI tract need to be evaluated. Incorporate polymer properties into the dissolution method development (gel formation of the polymer, floating of particle/dispersion particles, solid clinging to paddles/shafts/glassware). Test supersaturation over biologically relevant time frames in biorelevant media to determine if the API will stay in solution or crystallize out. Food effects need to be evaluated; specifics on fasting times and postdose feedings need to be detailed in reported studies. Dose range-dependent sink conditions along the GI tract (pH, volumes, and residence times) need to be considered and investigated; these will be dependent on the solubility of the API and the amorphous solid dispersion. pH effects of polymers, especially polymers used for enteric coatings, need to be evaluated throughout the entire GI tract. Investigate the use of alternative animal models, such as pigs and minipigs, that are a better model for nonprimate studies. Determine if APIs are substrates for human transporters and/or metabolizing isoforms and the affect this will have on absorption. For highly lipophilic molecules, lymphatic absorption and not only blood absorption need to be determined in early studies; use extended GITA model to predict regions of optimal absorption; use feedback from in silico models to help refine formulations.

phous solid dispersions, the goal will be to predict performance; therefore, it is recommended that dissolution parameters be chosen to mimic the biological systems and provide an IVIVR. Method development will include decisions on the appropriate apparatus, the media used to mimic biological conditions, and sink versus nonsink conditions. A number of studies show that the two-phase dissolution method employing both gastric and intestinal fluids can successfully predict the performance for oral solid forms.81–83 It is also important to match the media with the proposed delivery route. In one study using suppositories, it is postulated that the lack of IVIVR was due to the smaller amount of in vivo fluid available in the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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animal model (rabbit) compared with that used in the dissolution test.37 Use of simulated colonic fluid113 during the dissolution testing may also have helped the IVIVR. Dissolution methods to better mimic in vivo factors such as mixing and agitation due to the muscle layers have also been developed and need to be considered for routine use.91–96 The presence of a high amount of polymer in solid amorphous dispersions can also play an important role in designing the dissolution experiment. Many polymers have very different properties compared with APIs and excipients and these need to be incorporated into the method development. Physical characteristics114 such as gel formation of the polymer, floating of polymer/dispersion particles on top of the dissolution media, and polymer/dispersion particles clinging to paddle shafts or glassware, need to be investigated early in order to incorporate best practices and develop an effective method. As discussed above, the polymers can also have a secondary effect that will result in crystallization inhibition and extended supersaturation. Understanding the extent of this supersaturation advantage can be easily incorporated into the method development and it is recommended that time frames similar to those observed in biological systems (as outlined in Table 3) be used for method development and that possible precipitation be evaluated. Dissolution times of 30–60 min will be somewhat representative of gastric residence time but will provide no information on the time spent in the rest of the GI tract. Precipitation of the drug during an in vivo study may significantly affect performance, especially for poorly soluble drugs. When considering dissolution media for amorphous dispersions, it is important to consider not only the solubility characteristics of the drug but to also consider the dissolution characteristics for the polymer, especially in the case of pH-sensitive enteric polymers,39,44–47 such as polymethacrylates (Eudragit L and S) and HPMC derivatives (HPMCAS and HPMCP), which are insoluble in gastric fluid but dissolve rapidly in intestinal fluid. Using a gastric pH range around 2 to determine the dissolution of dispersion made with an enteric polymer that dissolves at neutral pH will be difficult to relate back to in vivo studies. An example to consider uses itraconazole, a weak base, and dispersions made with HPMC and Eudragit E-100.44–47 Dissolution studies performed in SGF without enzymes showed a significantly faster dissolution rate for the Eudragit E-100 amorphous solid dispersions versus the HPMC amorphous solid dispersions because the Eudragit E-100 is soluble in gastric fluid below pH 5. However, the Eudragit E-100 amorphous solid dispersions demonstrated a lower human bioavailability compared with the HPMC amorphous solid dispersion. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

The use of surfactants is also a consideration. They are commonly used when trying to increase solubility and achieve sink conditions. However, on the basis of desire to mimic GI conditions, it is our recommendation that it is better to go with simulated media as described previously.77 Sink versus nonsink conditions will continue to be an area of discussion for dissolution methods. For differentiating lot-to-lot variations, sink conditions are recommended by regulatory agencies. However, sink conditions in a dissolution bath are not relevant to physiological systems where competing processes such as absorption and regional differences in GI volumes may act to influence the actual supersaturation solubilities and dissolution rates. For comparison to in vivo data, it is suggested that different sink and nonsink conditions be investigated to achieve an IVIVR.

In Vivo Evaluation Drug candidates often fail in Phase I clinical trials because of poor oral bioavailability, whereas a lack of in vivo efficacy or unexpected toxicity tend to be the predominant reasons for failures in Phase II and III clinical testing.115 It is becoming more obvious that important factors are not consistently predicted or observed based on current preclinical screening studies. This indicates that better early in vitro and in vivo models are required in preclinical development to characterize the physicochemical properties, bioavailability, and predict the developability of new chemical entities. There is significant interest in the utility of amorphous solid dispersions for early and late studies, yet our limited survey of the literature showed that bioavailability improvement was not obtained in eight out of the 40 reports reviewed. As discussed previously, crystallization in the GI tract and unoptimized dissolution parameters could be playing a role. However, another possible reason is that little is known about the effects of physiology upon the clinical performance of amorphous solid dispersions. This fact prompts us to end our Commentary with suggestions concerning the in vivo considerations that need to be evaluated prior to clinical testing in order to reduce clinical attrition. The driving force for developing amorphous dispersion systems is the ability to increase the apparent solubility and subsequent absorption, which leads to increased bioavailability. One limitation of current dissolution and solubility testing is that they often do not accurately mimic clinical (biorelevant) conditions found in the patient.88 Improvement of predictive IVIVR/IVIVC between dissolution testing and observed bioavailability will only be fully realized by incorporating the critical physiological factors that DOI 10.1002/jps

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Table 7.

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Representative Factors for Amorphous Solid Dispersion Formulations on Absorption/Bioavailability Due to Increased Solubility

Properties

Factors

Physicochemical Lipophilicity

Stability

Ionization

Size Solubility limited

Formulation

Surface area increase (particle size reduction) Excipients

Dissolution limited

Physiological

Lumen contents

Epithelium

Lipid bilayer

Observations

Effect on Bioavailability (BA)

Relationship between increasing lipophilicity and absorption is parabolic.

High lipophilicity—API stays in membrane or depots in fat with small increase in BA; moderate increases BA; low lipophilictydepends on polarity, slight increase in BA. Physical stability (solid state) is poor; compound Decrease BA may nucleate to a crystalline form. Depends on the region of release. Can increase Chemical stability is generally poor in the BA if released in region with optimal stability formulation and/or in solution as a function of or decrease where API is unstable. pH; absorption of the API will depend on regional pHs. Increased solubility of the charged API Decrease in BA by passive transcellular route depending upon pH; weak bases would have when solubility is increased for the ionized solubility problems at a higher pH, and drug. Amorphous form release needs to be conversely weak acids at a lower pH. regionally targeted in the GI tract. There is an inverse reciprocal relationship In general, larger molecules have lower BA. between molecular size and permeability. Dissolution and permeability are normally fast. When solubility controls the BA, the gut can become saturated with API and increasing dose will not effect BA. For an amorphous form where the compound can maintain the supersaturated state, it would be possible to overcome the solubility-limited absorption. Increases the solubility. Poorly soluble compounds will demonstrate increased BA, dependent upon lipophilicity. Lipophilic excipients

May decrease dissolution and BA (e.g. lubricants), although lipid drug delivery systems can increase BA. Disintegrants can increase dissolution Generally increase BA, depending on the API’s physicochemical properties. Binders have the opposite effect of disintegrants. Generally can decrease BA by restricting dissolution. Surfactants can increase solubility and Surfactants can lower surface tension, form permeability, can be used in dispersions. micelles and increase BA; can interact with MDR transporters to increase BA (see below). Polymers can increase solubility, can also be Can increase BA; however, API-polymer used to generate dispersions or co-crystals interactions can also lower BA. Higher concentrations of polymers can reduce release rate and potentially lower BA. Tdiss is greater than the small intestine BA can increase with increasing dose; excipient changes may increase dissolution and BA. residence time. Permeability and solubility can be fast. Depending on the region, lipophilic APIs may be The gastrointestinal fluids can change sequestered in lipid/bile micelles. This may regionally; pH varies along the GI tract; flora alter BA in an unpredictable manner. Uptake and components such as bile salts also vary; by flora lowers BA. Differences in BA effects food can dramatically vary environment; are API dependent. Biorelevant dissolution cellular debris and mucus also present. media is limited in modeling the luminal contents. The complex mucus and glycocalyx layer is not The nature of the mucus and glycocalyx can effectively modeled in traditional in vitro cell limit the BA of lipophilic solutes. It also can alter the pH at the membrane surface due to lines. buffering effects. Contents of the lipid bilayer can vary This effect is often overlooked. The lipid bilayer significantly based on diet. Parallel artificial is composed of fatty acids incorporated into membrane permeability assays (PAMPA) phospholipids. There is also a polarized may help assess the net effect on passive distribution of phospholipids, with some transcellular permeation. phospholipids such as phosphatidylserine and phosphotidylethanolamine appearing only on the inner leaflet of the bilayer. Charge effects can alter BA. (Continued)

DOI 10.1002/jps

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Table 7.

Continued.

Properties

Factors Efflux transporters

Influx transporters

Metabolism

Permeability limited

Observations

Effect on Bioavailability (BA)

Can result in multidrug resistance [e.g., P-glycoprotein (Pgp), multidrug resistance-like transporters (MRPs)] and limit permeability when present on the luminal facing membrane or increase it when on the basal facing membrane. Can act in concert depending on substrate affinity and capacity. Function through a Michaelis–Menten saturable process, thus increasing solubility; can increase permeability. Excipients can also disrupt the function of some isoforms.

The main concern for BA is usually with luminal facing efflux pumps that can limit pump and absorbed substrate from the cytoplasm back into the lumen, thus reducing permeation of an API. The primary focus on ABC efflux pumps is on the Pgp, BCRP, and MRP1 and 2 isoforms; however, approximately 50 ABC transporters have been identified. There are also a number of SLC transporters that work to efflux drugs from the cytoplasm into the extracellular space, [e.g., organic anion transporter (OAT) isoforms]. Increases the BA of more polar APIs. The Influx transporters can increase the general substrates for an influx permeability of a variety of substrates, transporter seldom require amorphous normally polar. dispersions. Reduces BA by removing the API and making Normally result in the formation of it more polar for excretion. Amorphous chemically modified metabolites that are dispersions can increase the absorption of more polar than the API for excretion. lipophilic compounds by the passive There are two major forms of metabolism: transcellular pathway and increase the Phase I that results in chemical potential to saturation of metabolizing modification of an API through several enzymes in the GI epithelium and different pathways (e.g., deamidation or potentially the liver, thus increasing the oxidation) and Phase II results in chemical BA. conjugates (e.g., glucuronidation) The permeability across the epithelial barrier Amount of drug absorbed increases with an increasing dose via the passive will remain low regardless of the solubility. transcellular pathway. Amorphous Dissolution can be fast, particularly for dispersions can increase the BA. dispersions.

impact in vivo dissolution, including modifying solubility and dissolution methods to utilize more relevant media, and by optimizing permeability models that are superior to the current cell lines that possesses inherent variability.88,116–119 In Table 7 we have summarized several of the rate-determining physiological factors that influence the clinical performance of an amorphous dispersion that require greater consideration in preclinical testing. Central to amorphous solid dispersion performance will be the extent to which a variety of factors influence both the extent of supersaturation and permeability in the GI tract. The physiological diversity of GI fluids, particularly in fasted and fed states, presents a major issue when associated with defining sink conditions. The physical considerations associated with in vitro dissolution tend to be apparatus dependent and are not directly relevant to in vivo bioavailability controlling factors.120 The fact that fluid volumes are nonhomogeneously distributed throughout the GI tract, unlike a homogeneous dissolution bath, is an issue considering that the Noyes–Whitney equation relies in part on the assumption that the GI fluid is uniform in composition and continuously distributed under sink conditions. Clearly, regional GI fluid composition and volume changes may potentially impact soluJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

bility and dissolution differently along the GI tract compared with what is observed in a dissolution bath.87,101,102,121,122 It is also important to note that since solubility may differ across media and as a function of time (Table 3), the apparent thermodynamic equilibrium solubility must be appropriate for assessing dose rangedependent sink conditions along the GI tract. When considering poorly soluble BCS Class II and IV drugs for amorphous dispersions, it is critical that the role of free physiological water volumes on regional absorption is also considered.123 Simulating GI tract conditions are important from a biorelevancy and regulatory point of view as well. According to the FDA,88 a biorelevant product is defined as follows: “A drug product designed, developed and manufactured according to Quality Target Product Profile with specification (such as dissolution/release acceptance criteria) consistent with the desired in vivo performance of the product.” More simply stated, biorelevancy is based on the premise of “linking process, product, and patient for patient benefit.”88 Biorelevancy is an important consideration on several levels and needs to part of the drug development plan. There are a number of regional differences in fluid composition along the GI tract leading to significant physiological diversity that testing methods are DOI 10.1002/jps

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trying to reproduce. Volumes in the stomach can be changed significantly in the fasted versus fed states, which will alter the extent of dissolution. Traditionally, the focus has been placed on longer residence times and pH variations for drug release in the fed state. However, it is recommended that other factors be considered upon feeding, such as ionic species, bile salts, buffer capacity, and so on that can alter the dissolution process or the dissolved state of the drug.86,108 Fed and fasted states are also managed differently, as seen in our survey where a variety of fasting and postfeeding times were reported (Figs. 4a and 4b). Taken together, food effects can have a profound effect on in vivo drug product performance as illustrated in Figure 5 and it is suggested that this factor be considered when using amorphous solid dispersions in in vivo testing. Animal studies are usually performed under controlled diets to reduce potential confounding factors that might arise, particularly drug–nutrient interactions. In a controlled clinical setting, a human trial may also be managed under controlled conditions. However, this is certainly not the case for most human patients, particularly when one considers dietary diversity on a global scale. These differences in diet can affect the average residence times in the GI tract and may drastically alter gastric emptying rates. Fluid volumes between humans and most animals also differ and prefeeding and postfeeding times will also have a potential effect on gastric emptying rates and bioavailability.87,101,108,120 Furthermore, interindividual variations due to environmental, genetic, and dietary factors are often observed in humans.19 This is often not the case when using homogeneous animal model strains for preclinical testing. Factors including dissolution media composition and volume, measurement times that reflect actual residence times in the region, rates of competing nucleation, and apparent solubility changes in each region will impact the in vivo dissolution of amorphous dispersions and ultimately the product performance. The complexity of physiological factors associated with the predictions of human bioavailability significantly increase when species differences are considered in the preclinical in vivo PK screening studies. Comprehensive reviews contrasting the GI characteristics across commonly used animal models in pharmaceutical screening can serve as a good reference for species selection for oral formulations and compared with humans.124,125 Several common species that are used to investigate and estimate human bioavailability are mouse, rat, rabbits, dogs, and monkeys (Fig. 3).98,126 Changes along the GI tracts of the rats and dogs appeared to vary more when compared with human values, whereas the pig, another nonprimate species increasingly being used in safety pharmacology studies, was more similar to DOI 10.1002/jps

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Figure 5. Representative physiological rate-determining factors that can impact the extent of oral bioavailability observed for a drug: (a) general overview of the function of drug transporters and metabolizing enzymes present in the GI epithelial cells, (b) net permeation/absorption of drugs across a cell barrier is the sum of the permeability coefficients via each parallel pathway, and (c) a number of additional physiological factors that can influence the amount of free drug available for absorption.

humans.91–97,124 Monkeys actually had higher variability than any other species when compared with JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

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Table 8.

Transporter and Enzyme Interactions for Drugs in Survey

Drug Albendazole Cyclosporine A Esomeprazole Zn Fenofibrate Frusemide (Furosemide) Halofantrine Indomethacin Itraconazole Ketoconazole Lonidamine Nifedipine Nimodipine Nitrendipine Pranlukast Ritanovir Lopinavir Tacrolimus Tolbutamide

BCS class

BDDCS

Potential Transporter

Enzyme Interactions

2 2 4 2 4 NA 2

2 2 3 2 4 NA 2

2 2 2 or 4 low solubility 1 2 2 2 or 4 low solubility 4 4 2 2

2 2 NA 2 2 2 NA 2 2 2 2

NA P-gp NA P-gp, 1 URAT1 URAT, hNPT4 NA OAT 1 and 3, OCT 1 and 2, MRP isoforms BCRP, P-gp BCRP, P-gp MCT1 CYP3A4 BCRP, hENT2 BCRP, hENT2 NA BCRP, P-gp, MRP-1 P-gp, MRP-2 BCRP, P-gp NA

CYP3A4, CYP2J2 CYP3A4, CYP3A5, CYP3A7 CYP2C9, CYP2C19, CYP3A4, CYP2C9 NA CYP2D6, CYP3A4, CYP3A5 CYP2C9, CYP2C19, (CYP2D6 and CYP1A2 minor) CYP3A4 CYP2C19, CYP3A4 NA NA CYP3A4 CYP3A4 CYP3A4 CYP2D6, CYP3A4, CYP3A5 CYP3A4 CYP3A4, CYP3A5 CYP2C9

NA, not available; hNPT4/SLC17A3, human sodium phosphate transporter 4; P-gp, P-glycoprotein; URAT1, urate transporter 1; uridine diphosphate UGP, glucuronosyltransferases (UGTs).

humans, with stomach pH ranges of 4.7–5.0 being normal.124 This is important when considering the effects that can occur with weak acids and weak bases during development. To illustrate this, several studies have reported highly variable correlations between the human bioavailability and bioavailability determined in rodents, dogs, and monkeys for a number of compounds.126,127 The utilization of animal models to investigate bioavailability differences between amorphous dispersions of an API with their reference materials is critical to assess in vivo performance and potentially human clinical performance. It is recommended that the selection of a predictive animal model for testing the bioavailability of an amorphous dispersion should be made on a case-by-case basis, where the anticipated physiological rate-determining factors will dictate the selection of the species that is most analogous to humans for testing the specific compound. Furthermore, it is recommended that alternative animal models be investigated that may be underutilized despite their potentially higher physiological similarities to humans. For example, pigs and minipigs have been reported as a better model for nonprimate safety pharmacology studies89,97,98,127 and should be considered for future testing of amorphous solid dispersions. Modeling studies may also be useful when evaluating the in vivo performance of amorphous solid dispersions. The separation of different regions in the GITA model helps to account for regional changes and may enable better prediction of amorphous dispersion release using regionally targeted formulations, especially when using enteric coating polymers in the dispersions.128,129 Moreover, the data obtained

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from preclinical and regional in vivo absorption studies may be incorporated into in silico populationbased PK (PBPK) models including Simcyp103 or GastroPlus,130,131 where databases can be built and IVIVRs/IVIVCs can be evaluated in vitro, in vivo, or in silico using physiologically based PBPK models. It must be emphasized that in general the predictive capabilities of these programs increase with the relevant amount of in vivo data added. Thus, animal studies are essential for improving in silico-based predictive human PK and can aid in reducing clinical attrition. There have been a number of other absorption models that have been advanced for predicting absorption.105 It is suggested that continuous feedback from these programs be used to direct refinement of formulations that will ultimately improve upon clinical performance, particularly during later stages of clinical testing and throughout life cycle management. A number of other factors need to be considered for in vivo studies that involve processes after the drug has dissolved. First is the mechanism of absorption (Fig. 5). For highly lipophilic molecules, it is suggested that lymphatic absorption and not only blood absorption be considered during early screening studies to improve lead candidate selection and reduce clinical attrition.132,133 An extension of the GITA model can be used to predict regions of optimal absorption (absorption windows) where complex physiological factors can be used along with physicochemical properties to tailor dosage form design aimed at increasing bioavailability.99,102–104,134 Second is the role of transporters and drug metabolizing enzymes during the absorption process. Absorption may be impacted by the potential for drug–X interactions (X = DOI 10.1002/jps

ASSESSING THE PERFORMANCE OF AMORPHOUS SOLID DISPERSIONS

drug, food, endogenous substrate, and/or xenobiotic), as well as several other factors that need to be identified. An example is the marketed product Kaletra, an amorphous dispersion of lopinavir and ritonavir. In the Kaletra formulation, ritonavir is used to inhibit the CYP3A4 enzyme, which then increases the bioavailability of lopinavir.135,136 Table 8 reveals that many of the amorphous dispersion compounds reviewed were also substrates for human transporters and/or metabolizing isoforms. The effects of these variations cannot be ignored and need to be considered in utilizing the BCS model. Method standardization and placing a greater emphasis on the BDDCS might be merited to obtain better IVIVRs or IVIVCs. Third is variation in permeability testing to classify drugs in the BCS and BDDCS.137 It is recommended that careful consideration be given to the permeability/absorption model used to classify a compound because cell lines and tissue sections may offer different confounding variables, which can lead to different results and confuse early in vivo studies.119 The recently proposed Developability Classification System offers an opportunity to expand upon the BCS, and potentially the BDDCS. This system incorporates important factors that influence drug performance including the measurement of intestinal permeability and solubility in the context of formulation composition and its characteristics such as particle size.138 In summary, there are a number of physiologically relevant factors that need to be incorporated into the design of both in vitro and in vivo methods in order for a true IVIVR/IVIVC to be realized. In the amorphous solid dispersion papers that were surveyed, there were several issues that required greater consideration and were not fully discussed. First and foremost, a greater understanding of clinically relevant conditions needs to be incorporated into in vitro testing in order to enhance the predictability of developed IVIVRs/IVIVCs. Dissolution media and volumes also need to be closely monitored with respect to the fed and fasted states, particularly in the stomach. The regional effects of metabolism and active transport cannot be neglected as they impact the observed bioavailability in vivo. Cell models or permeability testing surrogates including tissue segments must also be characterized to determine the extent of their relevancy to the human in vivo region targeted for amorphous dispersion release. Furthermore, careful consideration of differences across the different species used require a greater understanding, including their GI physiology, GI regional fluid volumes and pHs, mixing forces, luminal compositions, dietary effects, roles of gender, and regional residence times comparative to those observed in humans. Animal models can offer a good prediction of human response provided they are carefully selected based on the desired research outcomes that are being sought. DOI 10.1002/jps

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CONCLUSION In this Commentary, we have attempted to consider the important factors that affect the therapeutic performance of amorphous solid dispersions from an in vitro and in vivo perspective and to make recommendations where possible. We have used a limited number of publications as a basis for describing a wide range of factors that can influence the stability and performance of dispersions. In particular, we wish to emphasize the importance of a greater understanding of the important physiological factors associated with the GI tract that play an important role in optimizing dissolution and bioavailability of API presented in solid dosage forms containing amorphous dispersions.

REFERENCES 1. Serrajuddin ATM. 1999. Solid dispersions of poorly watersoluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066. 2. Brouwers J, Brewster ME, Augustijns P. 2009. Supersaturating drug delivery systems: Answer to solubility-limited oral bioavailability. J Pharm Sci 98:2549–2572. 3. Bhugra C, Pikal MJ. 2008. Role of thermodynamic, molecular and kinetic factors in crystallization from the amorphous state. J Pharm Sci 97:1329–1349. 4. Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS. 2010. Understanding behavior of amorphous pharmaceutical systems during dissolution. Pharm Res 27:608–618. 5. Padden BE, Mill JM, Robbins T, Zocharski PD, Prasad L, Spence JK, LaFountaine J. 2011. Amorphous solid dispersions as enabling formulations for discovery and early development. Amer Pharm Rev 1:66–73. 6. Dobry DE, Settell DM, Baumann JM, Ray RJ, Graham LJ, Beyerinck RA. 2009. A model-based methodology for spraydrying process development. J Pharm Innov 4:133–142. 7. Breitenbach J. 2002. Melt extrusion: From process to drug delivery technology. Eur J Pharm Biopharm 54:107–117. 8. Shamblin SL, Taylor LS, Zografi G. 1998. Mixing behavior of colyophilized binary systems. J Pharm Sci 87:694–701. 9. Newman A, Engers D, Bates S, Ivanisevic I, Kelly RC, Zografi G. 2008. Characterization of amorphous API– polymer mixtures using X-ray powder diffraction. J Pharm Sci 97:4840–4856. 10. Pham TN, Watson SA, Edwards AJ, Chavda M, Clawson JS, Strohmeier M, Vogt G. 2010. Analysis of amorphous solid dispersions using 2D solid-state NMR and1 HT1 relaxation measurements. Mol Pharm 7:1667–1691. 11. Ta J, Sun Y, Zhang GGZ, Yu L. 2009. Solubility of small molecule crystals in polymers: D-Mannitol in PVP, indomethacin in PVP/VA, and nifedipine in PVP/VA. Pharm Res 26:855–864. 12. Sun Y, Tao Y, Zhang GGZ, Yu L. 2010. Solubilities of crystalline drugs in polymers: An improved analytical method and comparisons of solubilities of indomethacin and nifedipine in PVP, PVP/VA and PVAc. J Pharm Sci 99:4023–4031. 13. Matsumoto T, Zografi G. 1999. Physical properties of solid molecular dispersions of indomethacin with poly(vinyl pyrrolidone) and poly(vinyl pyrrollidone–co–acetate) in relation to indomethacin crystallization. Pharm Res 16:1722–1728. 14. Taylor LS, Zografi G. 1997. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res 14:1691–1698. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

1374

NEWMAN, KNIPP, AND ZOGRAFI

15. Hancock BC, Shamblin S, Zografi G. 1995. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperature. Pharm Res 12:799–806. 16. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS. 2008. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: An overview. Mol Pharm 5:1003–1019. 17. Curatolo W, Nightingale JA, Herbig SM. 2009. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res 26:1419–1431. 18. Rowland M, Towser TN. 1995. Clinical pharmacokinetics: Concepts and applications. 3rd Ed. Philadephia, Pennsylvania: Lippincott Williams & Wilkins, pp 2–6, 57–60, 95, and 99. 19. Elmquist WF. 2005. Targeted bioavailability: A fresh look at pharmacokinetic and pharmacodynamic issues in drug delivery. In Drug delivery: Principles and practices; Wang B, Siahaan T, Soltero R, Eds. Hoboken: John Wiley and Sons, Inc., pp 73–82. 20. Kalaiselvan R, Mohanta GP, Madhusadan S, Manna PK, Manavaian R. 2007. Enhancement of bioavailability and antihelmintic efficacy of albendazole by solid dispersions and cyclodextrin complexation techniques. Pharmazie 62:604– 607. 21. Kalaiselvan R, Mohanta GP, Manavaian R. 2006. The inhibition of albendazole solid molecular dispersions. Pharmazie 61:618–624. 22. Kohri N, Yamayoshi Y, Xin H, Iseki K, Sato N, Todo S, Miyazaki K. 1999. Improving the oral bioavailability of albendazole in rabbits by the solid dispersion technique. J Pharm Pharmacol 51:159–164. 23. Kennedy M, Hu J, Ga P, Li L, Ali-Reynolds A, Chai B, Gupta V, Ma C, Mahajan N, Akrami A, Surapaneni S. 2008. Enhanced bioavailability of a poorly soluble VR1 antagonsit using an amorphous solid dispersion approach: A case study. Mol Pharm 5:981–993. 24. Joshi HN, Tejwani W, Jemal M, Bathala MS, Varia SA, Serajuddin ATM. 2004. Bioavailability enhancement of a poorly water soluble drug by solid dispersion in a polyetyleneglycolpolysorbate 80 mixture. Int J Pharm 269:251–258. 25. Lakshman JP, Cao Y, Kowalski J, Serajuddin ATM. 2008. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm 5:994–1002. 26. Liu C, Wu J, Shi B, Zhang Y, Gao T, Pei Y. 2006. Enhancing the bioavailability of cyclosporine A using solid dispersion containing polyethylene (40) stearate. Drug Dev Ind Pharm 32:115–123. 27. Kushida I, Ichikawa M, Asakawa N. 2002. Improvement of dissolution and oral absorption of WR-34122, a poorly water soluble dual 5-lipoxygenase/cyclooxygenase inhibitor with anti-inflammatory activity by preparing solid dispersion. J Pharm Sci 91:258–266. 28. Xie Y, Xie P, Song X, Tang X, Song H. 2008. Preparation of esomeprazole zinc solid dispersion and study on its pharmacokinetics. Int J Pharm 360:53–57. 29. He H, Yang R, Tang X. 2010. In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion. Drug Dev Ind Pharm 36:681–687. 30. Doherty C, York P. 1998. The in vitro pH–dissolution dependence and in vivo bioavailability of frusemide–PVP solid dispersions. J Pharm Pharmacol 41:73–78. 31. Doherty C, York P. Mechanisms of dissolution of frusemide/ PVP solid dispersions. Int J Pharm 34:197–205. 32. Doherty C, York P. Accelerated stability of an X-ray amorphous frusemide–polyvinylpyrrolidone solid dispersion. Drug Dev Ind Pharm 15:1969–1987. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

33. Khoo S-M, Porter CJH, Charman WN. 2000. The formulation of halofantrine as either non-solubilising PEG 6000 or solubilising lipid based solid dispersions: Physical stability and absolute bioavailability assessment. Int J Pharm 205:65–78. 34. Chokshi RJ, Zia H, Sandhu HK, Shah NH, Malick WA. 2007. Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution—Pros and cons. Drug Del 14:33–45. 35. Chowdary KPR, Babu KVVS. 1994. Dissolution, bioavailability and ulcerogenic studies on solid dispersions of indomethacin in water soluble cellulose polymers. Drug Dev Ind Pharm 20:799–813. 36. Ohnishi N, Yokoyama T, Umeda T, Kiyohara Y, Kuroda T, Kita Y, Kuroda K. 1986. Preparation of sustained-release suppositories of indomethacin using a solid dispersion system and evaluation of bioavailability in rabbits. Chem Pharm Bull 34:2999–2304. 37. Ohnishi N, Kiyohara Y, Kita Y, Kuroda K, Yokoyama T. 1987. Effect of the molecular weight of polyethylene glycol on the bioavailability of indomethacin in sustained-release suppositories prepared with solid dispersions. Chem Pharm Bull 35:3511–3515. 38. DiNunzio JC, Brough C, Miller DA, Williams RO, McGinity JW. 2010. Fusion processing of itraconazole solid dispersions by KinetiSol dispersing: A comparative study to hot melt extrusion. J Pharm Sci 99:1239–1253. 39. DiNunzio JC, Miller DA, Yang W, McGinity JW, Williams RO. 2008. Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm 5:968–980. 40. Engers D, Teng J, Jimenez-Novoa J, Gent P, Hossack S, Campbell C, Thomson J, Ivanisevic I, Templeton A, Byrn S, Newman A. 2010. A solid-state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. J Pharm Sci 99:3901–3922. 41. Kapsi SG, Ayres JW. 2001. Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability. Int J Pharm 229:193–203. 42. Lee SL, Nam K, Kim MS, Jun SW, Park J-S, Woo JS, Hwang S-J. 2005. Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability. Arch Pharm Res 28:866–874. 43. Nam K-W, Lee S, Hwang S-J, Woo JS. 2002. Enhancing water-solubility of poorly soluble drug, itraconazole with water-soluble polymer using supercritical fluid processing(abstract #245). Proceedings of the Controlled Release Society, 29th Annual Meeting, July 20-25, Seoul, South Korea. 44. Six K, Daems T, de Hoon J, Van Hecken A, Depre M, Bouche M-P, Prinsen P, Verreck G, Peeters J, Brewster ME, Van den Mooter G. 2005. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur J Pharm Sci 24:179–186. 45. Six K, Leuner C, Dressman J, Verreck G, Peeters J, Blaton N, Augustjins P, Kinget R. 2002. Thermal properties of hot-stage extrudates of itraconazole and Eudragit E100. Phase separation and polymorphism. J Therm Anal Cal 68:591–601. 46. Six K, Berghmans H, Leuner C, Dressman J, Van Werde K, Mullens J, Benoist L, Thimon M, Meublat L, Verreck G, Peeters J, Brewster M, Van den Mooter G. 2003. Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion, Part II. Pharm Res 20:1047–1054. 47. Six K, Verreck G, Peeter J, Brewster M, Van den Mooter G. 2004. Increased physical stability and improved dissolution DOI 10.1002/jps

ASSESSING THE PERFORMANCE OF AMORPHOUS SOLID DISPERSIONS

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci 93:124–131. Heo M-Y, Piao S-S, Kim T-W, Cao Q-R, Kim A, Lee B-J. 2005. Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersions on enhanced dissolution and bioavailability of ketoconazole. Arch Pharm Res 28:604–611. Matsunaga N, Nakamura K, Yamamoto A, Taguchi E, Tsunoda H, Takahashi K. 2006. Improvement by solid dispersions of the bioavailability of KRN633, a selective inhibitor of vegf receptor-2 tryosine kinase, and identification of its potential therapeutic window. Mol Cancer Ther 5:80–88. Palmieri FP, Cantalamessa F, Martino PD, Nasuti X, Martelli S. 2002. Lonidamine solid dispersions: In vitro and in vivo evaluation. Drug Dev Ind Pharm 28:1241–1250. Kai T, Akayama Y, Nomura S, Sata M. 1996. Oral absorption improvement of poorly soluble drug using solid dispersion technique. Chem Pharm Bull 44:569–571. Law SL, Lo WY, Lin FM, Chang CH. 1992. Dissolution and absorption of nifedipine in polyethylene glycol solid dispersion containing phosphatidylcholine. Int J Pharm 84:161–166. Emara LH, Badr RM, Abd Elbary A. 2002. Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers. Drug Dev Ind Pharm 28:795– 807. Sugimoto I, Kuchiki A, Nakagawa H. 1981. Stability of nifedipine–polyvinylpyrrollidone coprecipitate. Chem Pharm Bull 29:1715–1723. Sugimoto I, Kuchiki A, Nakagawa H, Tohgo K, Kondo S, Iwane I, Takahashi K. 1980. Dissolution and absorption of nifedipine from nifedipine–polyvinylpyrrollidone coprecipitate. Drug Dev Ind Pharm 6:137–160. Uekama K, Uekama K, Ikegami K, Wang Z, Horiuchi Y, Hirayama F. 1992. Inhibitory effect of 2-hydroxypropyl-$cyclodextrin on crystal growth of nifedipine during storage: Superior dissolution and oral bioavailability compared with polyvinyl pyrrolidone K-30. J Pharm Pharmacol 44:73–78. Zheng X, Yang R, Zhang Y, Wang Z, Tang X, Zheng L. 2007. Part II: Bioavailability in Beagle dogs of nimodipine solid dispersions prepared by hot-melt extrusion. Drug Dev Ind Pharm 33:783–789. Zheng X, Yang R, Tang X, Zheng L. 2007. Part I: Characterization of solid dispersions of nimodipine prepared by hot-melt extrusion. Drug Dev Ind Pharm 33:791–802. Cui F, Yang M, Jiang Y, Cun D, Lin W, Fan Y, Kawashima Y. 2003. Design of sustained-release nitrendipine microspeheres having solid dispersion structure by quasi-emulsion solvent diffusion method. J Control Rel 91:375–384. Chono S, Takeda E, Seki T, Morimoto K. 2008. Enhancement of the dissolution rate and gastrointestinal absorption of prankulast as a model poorly water-soluble drug by grinding with gelatin. Int J Pharm 347:71–78. Verrek G, Vandecruys R, De Conde V, Baert L, Peeters J, Brewster M. 2004. The use of three different solid dispersion formulations—melt extrusions, film-coated beads, and a glass thermoplastic system—to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor. J Pharm Sci 93:1217–1228. Law D, Schmitt EA, Marsh KC, Everitt EA, Wang W, Fort JJ, Krill SL, Qiu Y. 2004. Ritanovir–PEG 8000 amorphous solid dispersions: In vitro and in vivo evaluations. J Pharm Sci 93:563–570. Law D, Krill SL, Schmitt EA, Fort JJ, Qiu Y, Wang W, Porter WR. 2001. Physicochemical considerations in the preparation of amorphous ritanovir–poly(ethylene glycol) 8000 solid dispersions. J Pharm Sci 90:1015–1025.

DOI 10.1002/jps

1375

64. Klein C E, Chiu Y-L, Awni W, Zhu T, Heuser RS, Doan T, Breitenbach J, Morris JB, Brun SC, Hanna GJ. 2007. The tablet formulation of lopinavir/ritanovir provides similar bioavailability to the soft–gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr 44:401–410. 65. Sheen P-C, Khetarpal VK, Cariola CM, Rowlings CE. 1995. Formulation studies of a poorly water-soluble drug, in solid dispersions to improve bioavailability. Int J Pharm 118:221–227. 66. Yamashita K, Nakate T, Okimoto K, Ohike A, Tkunaga Y, Ibuki R, Higaki K, Kimura T. 2003. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm 267:79–91. 67. Kedzierewicz F, Zinutti C, Hoffman M, Maindent P. 1993. Bioavailability study of tolbutamide g-cyclodextrin inclusion compounds. Solid dispersions and bulk powder. Int J Pharm 94:69–74. 68. Kedzierewicz F, Hoffman M, Maincent F. 1990. Comparison of tolbutamide $-cyclodextrin inclusion compounds and solid dispersions. Int J Pharm 58:221–227. 69. Kimura K, Hirayama F, Arima H, Uekama K. 2000. Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl$-cyclodextrin complex. Chem Pharm Bull 48:646–650. 70. Brown CK, Chokshi HP, Nickerson B, Reed RA, Rohrs BR, Shah PA. 2004. Acceptable analytical practices for dissolution testing of poorly soluble compounds. Pharm Tech. December issue: 56–64. 71. Food and Drug Administration. 2000.Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a Biopharmaceutics Classification System. Rockville, Maryland. 72. Food and Drug Administration. 1997.Guidance for industry: Extended release oral dosage forms: Development, evaluation, and application of in vitro/in vivo correlations. Rockville, Maryland 73. Loebenberg R, Amidon GL. 2000. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm 5:3–12. 74. Xia D, Cui F, Piao H, Cun D, Piao H, Jiang Y, Ouyang M, Quan P. 2010. Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats. Pharm Res 27:1965–1976. 75. Jantratid E, Janssen N, Reppas C, Dressman J. 2008. Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update. Pharm Res 25:1663–1676. 76. Mudie DM, Amidon GL, Amidon GE. 2010. Physiological parameters for oral delivery and in-vitro testing. Mol Pharm 7:1388–1405. 77. Bevernage J, Fortier T, Brouwers J, Tack J, Annaert P, Augustijns P. 2011. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm 8:564–570. 78. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. 2010. How to improve R & D productivity: The pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214. 79. General Chapters <711>, “Dissolution” and <724> “Drug Release.” 2004.In The United States Pharmacopeia 27– National Formulary 22. United States Pharmacopeial Convention, Inc., Rockville, Maryland, pp 2303–2304and 2305–2312. 80. Yu LX, Wang JT, Hussain AS. 2002. Evaluation of USP apparatus 3 for dissolution testing of immediate- release products. AAPS PharmSci 4, 1–5. 81. Carino SR, Sperry DC, Hawley M. 2010. Relative bioavailability of three different solid forms of PNU-141659 as JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

1376

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

NEWMAN, KNIPP, AND ZOGRAFI

determined with the artificial stomach-duodenum model. J Pharm Sci 99:3923–3930. Gao Y, Carr A, Spence JK, Wang WW, Turner TM, Lipari JM, Miller JM. 2010. A pH–dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: Application to physiologically based pharmacokinetic modeling. Mol Pharm 7:1516–1526. Polster CS, Stassi F, Wu S-Y, Sperry DC. 2010. Use of artificial stomach–duodenum model for investigation of dosing fluid effect on clinical trial variability. Mol Pharm 7:1533–1538. General Chapter <1092>. 2006. The dissolution procedure: Development and validation. In The United States 41Pharmacopeia 34–National Formulary 29. United States Pharmacopeial Convention, Inc., Rockville, Maryland. Supplementary Chapter I E. 1998.Dissolution of solid oral dosage forms.” In British Pharmacopeia1998, Vol. II, pp A327–A331. Fadda HM, Sousa T, Carlsson AS, Abrahamsson B, Williams JG, Kumar D, Basit AW. 2010. Drug solubility in luminal fluids from different regions of the small and large intestine of humans. Mol Pharm 7:1527–1532. Fadda HM, McConnell EL, Short MD, Basit AW. 2009. Mealinduced acceleration of tablet transit through the human small intestine. Pharm Res 26:356–360. Selen A. 2009. Biorelevant dissolution testing: Characterizing the product for the patient. short course #3: developing biorelevant dissolution test methods with an emphasis on QbD. Los Angeles, California: American Association of Pharmaceutical Scientists. Schiller C, Frohlich CP, Giessmann T, Siegmund W, Monnikes H, Hosten N, Weitschies W. 2005. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther 22:971– 979. Weitschies W, Wedemeyer RS, Kosch O, Fach K, Nagel S, S¨oderlind E. 2005. Impact of the intragastric location of extended rlease tablets on food interactions. J Control Release 108:375–85. Minekus M, Marteau P, Havenaar R, Huis In T Veld J. 1995. A multicomparmental dynamic computer-controlled model simulating the stomach and small intestine. Altern Lab Animals 23:197–209. Minekus M, Smeets-Peeters M, Bernalier A, Marol-Bonnin S, Havenaar R, Marteau P, Alric M, Fonty G, Huis In T Veld JH. 1995. A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products. Appl Microbiol Biotechnol 53:108–114. Garbacz G, Wedemeyer R-S, Nagel S, Giessmann T, M¨onnikes H, Wilson CG. 2008. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. Eur J Pharm Biopharm 70:421– 428. D’Arcy DM, Corrigan OI, Healy AM. 2006. Evaluation of hydrodynamics in the basket dissolution apparatus using computational fluid dynamics–dissolution rate implications. Eur J Pharm Sci 27:259–267. Wei JD, Ho HO, Chen CH, Ke WT, Chen ET, Sheu MT. 2010. Characterisation of fenofibrate dissolution delivered by a selfmicroemulsifying drug-delivery system. J Pharm Pharmacol 62:1685–1696. Garbacz G, Golke B, Wedemeyer R-S, Axell M, S¨oderlind E, Abrahamsson B. 2009. Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses. Eur J Pharm Sci 38:147–155.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012

97. Webster J, Bollen P, Grimm H, Jennings M. 2010. Ethical implications of using the minipig in regulatory toxicology studies. J Pharmacol Toxicol Methods 62:160–166. 98. Curtis MJ. 2010. The RETHINK project: Impact of toxicity testing in the minipig as an alternative approach in regulatory toxicity testing. J Pharmacol Toxicol Methods 62(3):157–162. 99. Kimura T, Higaki K. 2002. Gastrointestinal transit and drug absorption. Biol Pharm Bull 25:149–164. 100. Collins PJ, Horowitz M, Cook DJ, Harding PE, Shearman DJC. 1983. Gastric emptying in normal subjects—A reproducible technique using a single scintillation camera and computer system. Gut 24:1117–1125. 101. McLaughlan G, Fullarton GM, Crean GP, McColl KE. 1989. Comparison of gastric body and antral pH: A 24 hour ambulatory study in healthy volunteers. Gut 30:573–578. 102. Washington N, Washington C, Wilson CG. 2001.Physiological pharmaceutics: Barriers to drug absorption, 2nd Ed. London, UK: Taylor and Francis. 103. Jamei M, Turner D, Yang J, Neuhoff S, Polak S, RostamiHodjegan A, Tucker G. 2009. Population-based mechanistic prediction of oral drug absorption. AAPS J 11:225– 237. 104. Rostami-Hodjegan A, Tucker G. 2007. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Disc 6:140–148. 105. Huang W, Lee SL, Yu LX. 2009. Mechanistic approaches to predicting oral drug absorption. AAPS J 11:217–224. 106. Coupe AJ, Davis SS, Wilding IR. 1991. Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects. Pharm Res 8:360–364. 107. Podczeck F, Mitchell CL, Newton JM, Evans D, Short MB. 2007. The gastric emptying of food as measured by gammascintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions. J Pharm Pharmacol 59(11):1527–1536. 108. McConnell EL, Fadda HM, Basit AW. 2008. Gut instincts: Explorations in intestinal physiology and drug delivery. Int J Pharm 364:213–226. 109. Yu LX, Amidon GL. 2002. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res 19(7):921–925. 110. Wu CY, Benet LZ. 2005. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22:11–23. 111. Ashiru DAI, Patel R, Basit AW. 2008. Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females. Pharm Res 25:2327–2333. 112. Kabanov AV, Okano T. 2003. Challenges in polymer therapeutics: State of the art and prospects of polymer drugs. Adv Exp Med Biol 519:1–27. 113. Vertzoni M, Diakidou A, Chatzilias M, S¨oderlind E, Abrahamsson B, Dressman JB, Reppas C. 2010. Biorelevant media to simulate fluids in the ascending colon of humans and their usefulness in predicting intracolonic drug solubility. Pharm Res 27:2187–2196. 114. Puri V, Dantuluri K, Bansal AK. 2011. Investigation of atypical dissolution behavior of an amorphous solid dispersion. J Pharm Sci 100:2640–2648. 115. Rolan P, Danhof M, Stanskic D, Peck C. 2007. Current issues relating to drug safety especially with regard to the use of biomarkers: A meeting report and progress update. Eur J Pharm Sci 30:107–112. 116. Jantratid E, Janssen N, Reppas C, Dressman J. 2008. Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update. Pharm Res 25:1663–1676. DOI 10.1002/jps

ASSESSING THE PERFORMANCE OF AMORPHOUS SOLID DISPERSIONS

117. Volpe DA. 2010. Application of method suitability for drug permeability classification. AAPS J 12:670–678. 118. Volpe DA. 2008. Variability in Caco-2 and MDCK cell-based intestinal permeability assays. J Pharm Sci 97:712–725. 119. Yamashita S, Tachiki H. 2009. Analysis of risk factors in human bioequivalence study that incur bioinequivalence of oral drug products. Mol Pharm 6:48–59. 120. Abrahamsson B, Lennernas H. 2005.Application of the Biopharmaceutics Classification System now and in the future. Drug bioavailability: Estimation of solubility, permeability, absorption and bioavailability. In Methods and principles in ¨ H, Armedicinal chemistry; vanWaterbeemd H, Lennerhas tursson P, Eds. Vol. 18. Weinheim, Germany: Wiley-VCH. ¨ H. 1998. Human intestinal permeability. J Pharm 121. Lennerhas Sci 87:403–410. 122. Maury J, Nicoletti C, Guzzo-Chambraud L, Maroux S. 1995. The filamentous brush border glycocalyx, a mucinlike marker of enterocyte hyper-polarization. Eur J Biochem 228:323–331. 123. Sutton SC. 2009. Role of physiological intestinal water in oral absorption. AAPS J 11:277–285. 124. Desso JM, Williams AL. 2008. Contrasting the gastrointestinal tracts of mammals: Factors that influence absorption. Ann Rep Med Chem 43:353–371. 125. Kararli TT. 1995. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos 16:351–380. 126. Grass GM, Sinko PJ. 2002. Physiologically-based pharmacokinetic simulation modeling. Adv Drug Deliv Rev 54:433–451. 127. Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J, and under the auspices of the Steering Group of the RETHINK Project. 2010. The utility of the Minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods 62:196–220. 128. Kagan L, Hoffman A. 2008. Systems for region selective drug delivery in the gastrointestinal tract: Biopharmaceutical considerations. Expert Opin Drug Deliv 5:681–692.

DOI 10.1002/jps

1377

129. Johnson KC. 2003. Dissolution and absorption modeling: Model expansion to simulate the effects of precipitation, water absorption, longitudinally changing intestinal permeability, and controlled release on drug absorption. Drug Dev Ind Pharm 29:833–842. 130. Bolger MB, Lukacova V, Woltosz WS. 2009. Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine. AAPS J 11:353–363. 131. Lukacova V, Woltosz WS, Bolger MB. 2009. Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data. AAPS J 11:323–334. 132. Trevaskis NL, Charman WN, Porter CJ. 2008. Lipidbased delivery systems and intestinal lymphatic drug transport: A mechanistic update. Adv Drug Deliv Rev 60:702– 716. 133. Porter CJ, Charman WN. 2001. Intestinal lymphatic drug transport: An update. Adv Drug Deliv Rev 50:61–80. 134. Aoki Y, Morishita M, Asai K, Akikusa B, Hosoda S, Takayama K. 2005. Region-dependent role of the mucous/glycocalyx layers in insulin permeation across rat small intestinal membrane. Pharm Res 22:1854–1862. 135. van Waterschoot RA, ter Heine R, Wagenaar E, van der Kruijssen CM, Rooswinkel RW, Huitema AD, Beijnen JH, Schinkel AH. 2010. Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol 160:1224–1233. 136. ter Heine R, Van Waterschoot RA, Keizer RJ, Beijnen JH, Schinkel AH, Huitema AD. 2011. An integrated pharmacokinetic model for the influence of cyp3a4 expression on the in vivo disposition of lopinavir and its modulation by ritonavir. J Pharm Sci 100:2508–2515. 137. Benet LZ, Broccatelli F, Oprea TI. 2011. BDDCS applied to over 900 drugs. AAPS J 13:519–547. 138. Butler JM, Dressman JB. 2010. The developability classification system: Application of biopharmaceutics concepts to formulation development. J Pharm Sci 99:4940–4954.

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