From Molecule To Dose Form

From Molecule to Dose Form
Accelerated Bioavailability Enhancement

for Early Phase Molecules
A special article collection companion to the webinar

broadcast October 21st, 2015.
To view the webinar, click here
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Table of Contents
Introduction
Professor Juergen Siepmann, PhD
University of Lille, College of Pharmacy
pages 1-3
Strategies for formulating and delivering poorly water-soluble drugs

Journal of Drug Delivery Science and Technology, Volume 30, Part B,
December 2015, Pages 342-351
Marta Rodriguez-Aller, Davy Guillarme, Jean-Luc Veuthey, Robert Gurny
pages 4-13
Amorphous drugs and dosage forms

Journal of Drug Delivery Science and Technology, Volume 23, Issue 4, 2013,
Pages 403-408
H. Grohganz, K. Lbmann, P. Priemel, K. Tarp Jensen, K. Graeser,
C. Strachan, T. Rades
Recent developments in oral lipid-based drug delivery
Journal of Drug Delivery Science and Technology, Volume 23, Issue 4, 2013,
Pages 375-382
N. Thomas, T. Rades, A. Mllertz
pages 14-19
pages 21-28
Introduction
J. Siepmann1,2
1
2
Univ. Lille, F-59000 Lille, France
INSERM U 1008, F-59000 Lille, France
*correspondence:
Professor Juergen Siepmann, PhD
University of Lille, College of Pharmacy
INSERM U 1008
3 Rue du Prof. Laguesse
59006 Lille, France
Fax: +33-3-20964942
juergen.siepmann@univ-lille2.fr
Nowadays, one of the major hurdles to be faced during the development of innovative drug
products is the limited bioavailability of numerous drug candidates. This is in great part due to
the very low aqueous solubility of these compounds. Consequently, they do not have the time
to dissolve to a sufficient extent upon administration to the living organism. Importantly, only
dissolved drug is able to diffuse and cross major barriers in the human body, e.g. the mucosa
in the gastro intestinal tract. Thus, even if the chemical structure of the drug candidate is ideal
to allow for efficient interaction with its target (and cure the patient), the compound fails in
vivo, since it is not able to reach its site of action. A broad range of formulation approaches
has been proposed to overcome this crucial bottleneck, aiming at increasing the dissolution
rate of poorly water-soluble drugs upon administration into the living body.
In order to quantify the dissolution rate of a drug particle, the famous Noyes-Whitney
equation can be used [1,2]:
= ( )
(1)
where dc/dt is the dissolution rate; K is a constant; cs denotes the solubility of the substance,
and ct is the concentration of dissolved substance in the surrounding bulk fluid at time t. The
basic hypothesis is that the diffusion of individualized drug molecules, ions or atoms through
the liquid unstirred boundary layer surrounding the drug particle is the slowest step in the
Page 1
series of events occurring during drug particle dissolution [3]. Thus, this step (which is
illustrated in Figure 1) is rate limiting and governs the dissolution kinetics.
unstirred
layer
cs
ct
Figure 1: Schematic presentation of the mass transport process, which is often dominant during the
dissolution of a drug particle: The diffusion of individualized drug molecules/atoms/ions through the
unstirred liquid boundary layer surrounding the drug particle (adapted from [3]).
Nernst and Brunner [4,5] used Ficks first law of diffusion to quantify this diffusional mass
transport step and derived the following equation:
dM S D
=
(c s ct )
dt
d
(2)
where dM is amount of substance which dissolves in the time interval dt; S denotes the
surface area available for diffusion/dissolution; D is the diffusion coefficient of the drug
within the liquid unstirred boundary layer; d is the thickness of this layer; cs and ct are the
solubility of the drug in the bulk fluid and the concentration of dissolved drug in the bulk fluid
at time t, respectively.
Looking at the Nernst-Brunner equation (Equation 2), it becomes obvious that different
strategies can be used to increase the dissolution rate of a drug. In particular, one can aim at:
(i) increasing the surface area available for dissolution via a reduction of the particle size;
and/or (ii) increasing the apparent solubility of the drug in the surrounding environment, e.g.
Page 2
via transformation into a physical state with a higher energy. These first two strategies are
very often applied. Eventually, the aim might also be to keep the concentration of dissolved
drug in the surrounding bulk fluid low, e.g. by facilitating the subsequent drug transport away
from its site of dissolution. On the other hand, the thickness of the liquid, unstirred boundary
layer as well as the diffusion coefficient of the drug in this layer are generally very difficult to
alter in practice in the human body.
This ebook is a selection of articles published in the Journal of Drug Delivery Science and
Technology, giving overviews on different types of strategies that are used to increase the
dissolution rates of poorly water-soluble drugs in order to increase their bioavailability. A
variety of practical examples are given and limitations of the different approaches are
discussed. The article of Grohganz et al. reviews the current state of the art in the field of
amorphous drug forms. The basic idea is to provide the drug in a physical form with a high
energy (and, thus, higher apparent solubility). However, recrystallization during long term
storage is a major concern, which needs to be addressed. The review article by Thomas et al.
gives a comprehensive overview on the latest developments in oral lipid-based drug delivery
systems. Briefly, in these cases highly lipophilic drugs are dissolved in lipid dosage forms,
thus, avoiding the drug dissolution step in the human body (or in other words: the apparent
drug solubility in the dosage form is so much increased that the entire drug dose is already
dissolved). Finally, the article by Rodriguez-Aller et al. gives a comprehensive overview on
the broad variety of approaches used to better formulate poorly water-soluble drugs, including
many examples of drug products which are available on the market.
References
[1] Noyes, A.A., Whitney, W.R., 1897. The rate of solution of solid substances in their own
solutions. J. Am. Chem. Soc. 19, 930-934.
[2] Noyes, A.A., Whitney, W.R., 1897. Ueber die Aufloesungsgeschwindigkeit von festen
Stoffen in ihren eigenen Loesungen. Z. Physikal. Chem. 23, 689-692.
[3] Siepmann, J., Siepmann, F., 2013. Mathematical modeling of drug dissolution. Int. J.
Pharm. 453, 12-24.
[4] Nernst, W., 1904. Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen. Z.
Phys. Chem. 47, 52-55.
[5] Brunner, E., 1904. Reaktionsgeschwindigkeit in heterogenen Systemen. Z. Phys. Chem.
47, 56-102.
Page 3
Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Contents lists available at ScienceDirect
Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst
Strategies for formulating and delivering poorly water-soluble drugs

Marta Rodriguez-Aller, Davy Guillarme, Jean-Luc Veuthey, Robert Gurny*
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest Ansermet, 1211 Geneva 4, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 March 2015
Received in revised form
12 May 2015
Accepted 12 May 2015
Available online xxx
Water solubility is a key parameter in drug formulation since it highly inuences drug pharmacokinetics
and pharmacodynamics. In the past decades, the challenge with poorly water soluble drugs has been
growing continuously. As a matter of fact, poorly soluble compounds represent 40% of the top 200 oral
drugs marketed in the US, 33% of drugs listed in the US Pharmacopeia, 75% of compounds under
development and 90% of new chemical entities. The present article presents and discusses the pharmaceutical strategies available to overcome poor water solubility in light of nal drug product examples.
First, chemical modications based on the adjustment of the pH and the design of prodrugs are presented and discussed. Physical modications based on modied solid states of the drug, small drug
particles, cosolvents, surfactants, lipids and cyclodextrins are discussed in a second part. Finally, the
option of modifying the route of administration is briey presented.
2015 Elsevier B.V. All rights reserved.
Keywords:
Insoluble drugs
Formulation
Delivery
pH
Pharmaceutical strategies
Alternative administration route
1. Introduction
The water solubility of drugs strongly inuences their pharmacokinetics and pharmacodynamics and is a key parameter for
formulators. Drug solubilization is based on the breaking of some
drugedrug and waterewater interactions for the creation of new
drugewater interactions. The strength of such interactions determines the solubility of a drug in water. Water solubility is one of
the main parameters of the biopharmaceutical classication system
(BCS) of drugs, as illustrated in Fig. 1A [1]. Moreover, Lipinski's rule
of 5 considers the solubility of drug candidates in view of the
rejection of inappropriate candidates at early stages of the drug
discovery process [2].
In the past decades, the challenges linked to poor water solubility have been continuously growing. The surge of combinatorial
chemistry and high throughput miniaturized screening methods
for drug discovery have resulted in an increase in molecular weight
and lipophilicity of drug candidates [3e5]. In addition, the push
towards increasing the potency of drugs often resulted in an increase in their lipophilicity (leading to stronger interactions with
their receptors). Currently, poorly soluble compounds represent
approximately 40% of the top 200 oral drugs marketed in the US
and Europe, as shown in Fig. 1B [6]. In addition, they represent 90%
* Corresponding author.
E-mail address: robert.gurny@unige.ch (R. Gurny).
of new chemical entities, 75% of compounds under development

and 33% of drugs listed in the US Pharmacopeia [2,3,6e11].
Interestingly, a variety of pharmaceutical strategies have been
designed to address the formulation and delivery challenges presented by poorly soluble drugs, these are reviewed and discussed in
the present article.
2. Strategies for formulating and delivering poorly watersoluble drugs
The pharmaceutical strategies to address the poor water solubility of a drug can be organized into three categories according to
the nature of the modication involved: the chemical, physical and
administration strategies, as illustrated in Fig. 2. These approaches
can of course be used separately or combined.
Over the past decades, many efforts have been made to improve
the formulation and delivery of poorly water-soluble immunosuppressants, prostaglandins and antineoplastic agents, which will
often be used as examples in the following sections.
It is worth mentioning that colloidal systems represent a more
recent option for the formulation of poorly water soluble drugs that
can involve chemical or physical modications [12]. Thus, colloidal
systems can be found in the sections describing prodrug design,
small drug particles and surfactant-lipid-based formulations. The
prodrug design can include drug-polymer nanoparticles and drug
covalent link to inorganic nanoparticles. The use of small drug
particles can involve nanocrystals and the use of nanoparticles for
http://dx.doi.org/10.1016/j.jddst.2015.05.009
1773-2247/ 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: M. Rodriguez-Aller, et al., Strategies for formulating and delivering poorly water-soluble drugs, Journal of Drug
Delivery Science and Technology (2015), http://dx.doi.org/10.1016/j.jddst.2015.05.009
M. Rodriguez-Aller et al. / Journal of Drug Delivery Science and Technology xxx (2015) 1e10
Fig. 1. A) The biopharmaceutical classication system (BCS) and B) the solubility of the top 200 marketed oral drugs in the US and Europe (adapted from [6]).
drug loading or adsorption. Finally, the surfactant and lipid formulations could include nanoemulsions, micelles, liposomes or
solid lipid nanoparticles.
2.1. Chemical modications
2.1.1. pH adjustment
The pH can inuence the solubility of a drug by affecting its
degree of ionization as a function of its pKa. In its ionized form, a
drug has a higher solubility than at its neutral form. However, drugs
are generally neutral at physiological pH. Thus, the pH of the
formulation can be adjusted with buffering excipients to ensure the
presence of the most soluble form of the poorly water-soluble drug.
For solid dosage forms, the buffering excipients control the pH
of the microenvironment surrounding drug particles during in vivo
dissolution [13]. Kranz and coworkers achieved a constant pHindependent release of the immunosuppressant, ZK811752, by
adding organic acids to the nal composition of the tablets [14].
The pH adjustment is a simple approach and represents a rstline strategy for the formulation of insoluble drugs. It is frequently
Fig. 2. A schematic representation of the different strategies for formulating and

delivering poorly water-soluble drugs.
combined with other solubilizing approaches such as surfactants,

cyclodextrins or cosolvents. The pH of the nal formulation is
selected not only according to drug solubility, but also considering
its tolerance, bioavailability, efcacy and stability, which can
strongly depend on the pH. In addition, the potential risk of drug
precipitation after administration needs to be considered.
2.1.2. Prodrug design
A prodrug can be dened as an inactive, chemically modied
version of a parent drug displaying improved physico-chemical
properties and being able to generate the active parent drug
through a rapid biotransformation. Two main prodrug design
categories can be identied: i) carrier-linked prodrugs where the
parent drug backbone is covalently linked to a prodrug moiety and
ii) bioprecursor prodrugs which are modied parent drugs with
functional groups requiring hydration or redox reactions, as illustrated in Fig. 3A. In addition, pre-prodrugs or double prodrugs
combine two prodrug design approaches in their design (carrierlinked and/or bioprecursor), one example being illustrated in
Fig. 3B.
The prodrug strategy has been gaining interest in the past years
and today its usefulness in drug formulation is unquestionable.
Prodrugs represent 10% of worldwide marketed drugs and were
33% of the small active molecules approved in 2008 [15,16]. Prodrug
design represents a versatile and powerful approach that can solve
a large variety of issues related to drug solubility, absorption, distribution, metabolism, toxicity or stability, among others [17,18].
The prodrug bioconversion is of major importance and needs to
be carefully evaluated and optimized. Ideally, the prodrug should
have an in vitro half-life one million times higher than its in vivo
half-life. Such a difference is only possible with enzyme-based
biotransformations [19].
For Anderson and Conradi, the prodrug of a poorly water soluble
drug should not be limited to the covalent link of a promoiety to the
parent drug, but should represent a new and optimized drug delivery system of its own [19]. In this sense, the use of prodrugs to
address the challenges with poor water-solubility will be discussed
through a number of examples, covering both the carrier and bioprecursor approaches.
For carrier-linked prodrugs, the rst type of prodrug design,
four main carrier moieties can be used: i) hydrophilic groups, ii)
hydrophobic groups, iii) amino acids and iv) macromolecules, as
illustrated in Fig. 3A. Carrier-linked prodrugs are frequently used to
simultaneously address the question of poor water-solubility of a
drug and achieve its targeted delivery.
The covalent linking of hydrophilic structures often confers a
higher solubility to the parent drug. Phosphate ester prodrugs are
Fig. 3. A) Prodrug design categories based on carrier-linked prodrugs and bioprecursors. B) Illustration of a pre-prodrug example combining the carrier-linked and bioprecursor
designs.
one of the most common examples for this group. Telzir and
Lexiva (GlaxoSmithKline, Brentford, UK) contain fosamprenavir,
the phosphate ester prodrug of the HIV protease inhibitor amprenavir. Fosamprenavir displays a water solubility 10 times higher
than amprenavir as well as an increased bioavailability, allowing a
simplication of the dosage regimen. With this prodrug formulation, the treatment went from 8 capsules twice a day to 4 tablets
once a day, which has a direct impact on patient quality of life and
compliance.
Hydrophobic structures can also be used to improve the
aqueous solubility of drugs. Their action is based on the disruption
of some drugedrug interactions (e.g. H-bounds) resulting in a
higher dissolution rate. The levodopa ethyl ester prodrug displayed
a higher solubility and absorption than the parent levodopa,
allowing its administration to Parkinson's disease patients as an
oral solution instead of the conventional tablets with known absorption issues [20]. Interestingly, this levodopa ethyl ester is a
double prodrug, levodopa being itself a prodrug of dopamine that
targets the central nervous system. The development of novel formulations for the anticancer drug 5-uorouracil (5-FU) based on
the prodrug approach has been intensively investigated to increase
its solubility, plasma half-life and selectivity. Xeloda (HoffmannLaRoche, Basel, Switzerland) contains capecitabine, which is a
double prodrug of 5-FU displaying an oral bioavailability close to
100% thanks to its high solubility, high absorption and low afnity
for the intestine thymidine phosphatases [21]. Interestingly, for
capecitabine design, hydrophobic hydrocarbon chains and amides
were covalently linked to the doxiuridine backbone, which is
already a pre-prodrug of 5-FU. After its oral absorption, capecitabine is biotransformed by carboxylesterases, deaminases and
tumor-specic thymidine phosphorylases, releasing the cytotoxic
5-FU specically in the tumor. Capecitabine combines the
advantages of an enhanced oral availability with a tumor-specic
activity [22e25].
The modications with amino acids can simultaneously achieve
two goals: increased water solubility and transporter-mediated
absorption (using amino acid transporters). The diversity in
physical properties of amino acids confers a high versatility to the
approach. An interesting example is valacyclovir, the L-valyl ester
prodrug of acyclovir marketed as Valtex (GlaxoSmithKline,
Brentford, UK). The bioavailability of valacyclovir is two times
higher than acyclovir due to its higher solubility and active transport via amino acid receptors [26]. After intracellular absorption,
valacyclovir is hydrolyzed, generating acyclovir, which requires
activation by viral thymidine kinase and cellular kinases to nally

inhibit herpes virus DNA polymerase. Valacyclovir can therefore
also be considered a pre-prodrug.
Finally, insoluble drugs can be combined with macromolecules.
Drug-macromolecule conjugates can: i) assist drug solubilization,
ii) decrease drug toxicity, iii) prevent drug degradation and iv)
achieve drug targeting [27,28]. Hyaluronic acid, polyethylene glycol
(PEG), hydroxypropylmetacrylamide (HPMA) and polyamidoamines or nitrodiol dendrimers are used in macromolecule prodrug
designs. HPMA is a versatile tool for the formulation of poorly
water-soluble drugs, such as anticancer agents (e.g. daunorubicine
or wortmannin), and is especially well suited for being combined
with drug targeting strategies [29e32]. Various HPMA conjugates
(with doxorubicin, paclitaxel, camptothecin or palatinate) have
gone through clinical trials [33]. In contrast to linear polymers,
dendrimers have branched structures that allow the linkage of
various drug molecules. They represent an interesting approach for
the formulation and delivery of insoluble drugs. De Groot and coworkers presented nitrodiol-based dendrimers for the targeted
release of the poorly water-soluble drug paclitaxel based on a single
tumor specic activation that triggers a cascade of reactions towards paclitaxel release [34]. The triggering reaction can be
designed to occur exclusively in the target tissue, allowing sitespecic drug release.
Regarding bioprecursor prodrugs, the second type of prodrug
design, an example is the Clinoril (Merck, New Jersey, US) oral
tablets, which contain sulindac, a non-steroidal anti-inammatory
drug [35,36]. Sulindac displays a 100-fold increased solubility and
improved oral absorption compared to its parent drug [37,38]. The
reduction of its sulphoxide group is necessary to generate the active
sulphide form.
The prodrug approach is therefore a powerful and versatile
strategy to not only address issues with poor water solubility, but
also to develop a myriad of strategies for efcient site-specic drug
delivery. Nevertheless, the stability of prodrug formulations can be
a hurdle since prodrugs require a high reactivity for a quick
biotransformation, but also need an excellent stability for a long
product shelf-life.
2.2. Physical modications
2.2.1. Modied solid state
Modifying the solid state of a drug inuences the strength of
drugedrug interactions, determining its solubility and dissolution
rate. In general, a higher structural disorder in the solid leads to

lower drugedrug interactions and a higher solubility.
When using modied solid states of a drug, formulators need to
nd a tradeoff between: i) the potential increase in drug solubility,
dissolution and/or availability and ii) potential stability issues. It is
very important to ensure that the selected drug state is not altered
during development, manufacturing and storage to guarantee that
patients receive the appropriate form of the drug. Special attention
needs to be paid to metastable polymorphs, salts, cocrystals and
amorphous forms that tend to recrystallize into their most stable
form. In addition, since the hydrated forms of a drug present a
lower stability and solubility than its pure crystal, the risk of the
drug form to be transformed into a hydrate needs to be evaluated.
The different modied solid forms illustrated in Fig. 4 can be
characterized as amorphous or crystalline (pure drug crystals,
polymorphs, hydrates, salts and cocrystals) according to their
disordered or ordered structures, respectively.
Crystalline modied drug forms include polymorphs, hydrates,
salts and cocrystals.
Drug crystal polymorphs are composed solely of the pure drug,
but different structures can lead to different drugedrug interactions and physico-chemical properties (e.g. density, melting
point, conductivity, solubility or stability). Metastable polymorphs
displayed a higher dissolution rate and solubility than the most
stable polymorphs having a positive impact on therapeutic efcacy,
as reported for cimetidine [39,40]. Besides, different polymorphs
were demonstrated to have different degradation and thermodynamic proles, some of which resulting in drug instability [41,42]. A
comprehensive screening and monitoring of the potential polymorphic transformations during the drug life-cycle is mandatory to
ensure drug quality, safety and efcacy [43].
Hydrates are crystalline drug structures that entrap water
molecules, facilitating close packaging and drugedrug interactions.
Generally, hydrates present limited pharmaceutical interest due to
their lower solubility, bioavailability and stability compared to the

anhydrous forms [41,44e47]. However, if a drug presents a high
tendency to form hydrates, the study and characterization of the
hydrated forms of the drug help to determine appropriate
manufacturing, packaging and storage conditions (particularly
important for hygroscopic drugs).
Crystalline salts are based on a proton transfer between an
ionizable group of the drug and a counter ion species. The resulting
salt modies the pH in the thin diffusion layer surrounding the
drug, resulting in an increased solubility compared to the
corresponding free form [48e50]. The counter ion species highly
inuences the solubility and must be carefully chosen [51]. Guzman
and coworkers demonstrated the higher solubility and availability
of the celecoxib sodium salt compared to its free form [52].
Cocrystals contain a drug and a cocrystal former, linked by Hbonds (different from salts in which a proton transfer takes place).
These H-bonds decrease the strength of the drugedrug interactions
compared to the pure drug crystal structure. The cocrystal
approach has been successfully used for drug dissolution and
bioavailability enhancement of poorly water soluble drugs [53e55].
This approach does not require the presence of ionisable groups on
the drug.
Amorphous solids are partially disordered solids where the
drugedrug interactions are weaker than in the crystals. They are
obtained either by preventing the formation of a crystalline structure or by disrupting an already existing crystal. Interestingly,
amorphous forms can theoretically present solubilities up to 1600
times higher than crystalline forms [56]. The amorphization is
usually combined with other small drug particle strategies such as
solid dispersions (explained in the following small drug particle
section). The solid dispersion of amorphous CsA particles in polymeric matrices was demonstrated to lead to a higher dissolution
rate and an improved bioavailability compared to crystalline CsA
[57,58]. In general, the solubility enhancement obtained with
Fig. 4. Different drug solid forms that can be used in formulations, including the most stable pure drug crystal, as well as polymorphs, hydrates, salts, cocrystals and amorphous
forms.
amorphization is higher than that achieved with metastable polymorphs [11]. However, amorphous forms can have a higher hygroscopicity, reactivity and instability.
2.2.2. Small drug particles
A decrease in particle size of poorly water-soluble drugs allows
i) the increase of the drug surface area and its dissolution rate, ii) an
improved bioavailability and iii) a reduced toxicity [58e69]. This
approach can be combined with any of the modied solid states
detailed above, cumulating the advantages of both strategies.
Fine and ultrane drug particles can be obtained using two
types of strategies: reducing the size of preexisting drug particles or
inducing drug solidication into small particles. The methods to
reduce the size of preexisting drug particles are based on cuts,
compression, impact, or attrition, or both impact and attrition [70].
The methods to form small drug particles are: hot-melt extrusion,
hot-melt encapsulation, spray drying and supercritical uid
methods. It is also worth mentioning another approach consisting
of the loading or supercial adsorption of poorly water-soluble
drugs into nanoparticles [12,71].
Small drug particles form a metastable system that needs to be
further stabilized to avoid agglomeration and crystalline growth. A
large number of excipients can be used as stabilizers acting by
electrostatic repulsion or steric stabilization (e.g. surfactants or
polymers) [11,72,73]. Different systems can be formed depending
on the environment surrounding the small particles: suspensions
and nanosuspensions are obtained when drug particles are in a
liquid environment, while solid dispersions are formed when the
drug particles are embedded in a solid matrix.
The advantages of using small drug particles for the formulation of poorly water-soluble actives are illustrated by the number
of marketed products that employ this strategy. Three marketed
formulations of the immunosuppressants sirolimus and everolimus used for the prevention of organ graft rejection can be
cited as examples. Rapamune (Pzer, New York, US) is an oral
tablet containing sirolimus nanocrystals (NanoCrystal technology, Elan Drug Technologies, Dublin, Ireland). Solid dispersion
strategies have been successfully used in the development of the
everolimus formulations Certican and Zortress (Novartis, Basel,
Switzerland).
2.2.3. Cosolvents
A cosolvent is a water-miscible organic solvent used to increase
the solubility of a drug in water. This approach is based on the
theory that the dissolution is enhanced when the solute and solvent have similar physicochemical characteristics. The most
important factor to be considered is the polarity of the mixture (i.e.
its dielectric constant). A large variety of cosolvents such as ethanol,
polyethylene glycol (PEG), propylene glycol (PG), glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethylsolfoxide (DMSO), as well as a number of oils (e.g. peanut, corn,
sesame, olive or peppermint) can be used [73,74]. The cosolvent
approach has been used for VePesid (Bristol-Myers Squibb, New
York, US) where the solubilization of the anticancer agent etoposide
was achieved with a mixture of PEG 400, citric acid, glycerin and
water.
This cosolvent strategy presents some limitations linked to i)
cosolvent taste and stability, ii) adverse physiological effects, iii)
potential modication of the pharmacokinetic prole of the drug
and iv) potential drug precipitation after administration. This
strategy remains a simple option frequently used in combination
with other solubilizing strategies for the formulation of poorly
water-soluble drugs. Nevertheless, the risks of drug instability, drug
precipitation and modication of the pharmacokinetic prole need
to be considered.
2.2.4. Surfactants and lipids

A surfactant is a surface-active agent that can stabilize interfaces.
A large variety of surfactants can be listed, from nonionics (e.g.
polyoxyethylene sorbitan fatty acid esters) to amphoteric (e.g. lecithins) and anionics (e.g. soaps, phospholipids). Cationic surfactants
(e.g. quaternary ammonium) are less common due to toxicity issues
and incompatibilities. Generally, a surfactant presents a polar head
and an apolar tail. As illustrated in Fig. 5, a fraction of the surfactant adsorbs to the interfaces present in the system (liquid-air or
liquideliquid interfaces), decreasing the interfacial tension and
stabilizing the system. This property is used for emulsion stabilization. When the surfactant is added at a concentration above its
critical micellar concentration, surfactant molecules self-assembly
into micelles, liposomes or other structures [75].
Micelles presenting a hydrophilic spherical shell composed of
polar heads and a hydrophobic core of apolar tails create an
appropriate environment to solubilize poorly water-soluble drugs,
as illustrated in Fig. 5A. Not all micelles are well suited for poorly
water-soluble drugs, as it is the case of inverse micelles. Polymeric
micelles deserve a special mention since they display interesting
properties such as: i) low critical micellar concentration, ii) slow
dissociation, iii) longer drug retention or potential increase in drug
half-life [76e82].
Liposomes are globular bilayer formations allowing the solubilization of poorly water-soluble drugs inside the bilayer, as
illustrated in Fig. 5B.
Emulsions are dispersions of two immiscible phases (typically
an oily phase and an aqueous phase) stabilized by a surfactant, as
illustrated in Fig. 5C, and are appropriate for the formulation of
lipophilic drugs [70]. The drug is solubilized in the oily phase,
which could be the dispersed or dispersant phase, leading to oil-inwater (o/w) or water-in-oil (w/o) emulsions. Two types of emulsions can be identied: i) conventional emulsions and ii) microemulsions. A conventional emulsion is thermodynamically
unstable needing an input of energy for its formation. Emulsion
droplets have a diameter higher than 100 mm, conferring a milky
aspect to the preparation. On the contrary, a microemulsion is
thermodynamically stable and the droplets have a diameter between 6 and 80 nm, which does not affect optical transparency. The
excipients and percentage of each phase play major roles in
emulsion formation and stabilization. Some commonly used oily
phases include vegetable oils, glycerols, fatty acids and their derivatives or glycerides. Microemulsions requiring further stabilization include a cosurfactant or a mixture of hydrophilic and
lipophilic surfactants in specic proportions.
Solid-lipid nanoparticles are another type of formulation based
on surfactants and lipids, which combine the advantages of liposomes, emulsions and nanoparticles [12,83].
Surfactant-related formulations can be divided into three
groups: i) a rst group with ready-to-use formulations, ii) a second
group with formulations requiring dilution in an aqueous vehicle
prior to administration and iii) a third group involving pro-formulations that readily form the nal emulsion or micelle system in
contact with the biological medium. The presented groups are
further discussed in light of examples of marketed products.
Ready-to-use formulations include emulsions or micelle formulations intended to be administered as such. This is the case for
Restasis (Allergan, California, US) a cyclosporine A o/w emulsion
developed for the topical treatment of dry eye syndrome.
The formulations requiring a dilution in water prior to
administration lead to the formation of: i) micelles, as in the case of
Sandimmune (Novartis, Basel, Switzerland) for the iv administration of cyclosporine A micelles, ii) liposomes, as for Visudyne
(Novartis, Basel, Switzerland) leading to verteporn liposomes or
iii) emulsions, as for Rapamune (Pzer, New York, US) leading to a
Fig. 5. Surfactant distribution and self-assembly structures in aqueous environment for the formation of A) a micelle and B) a liposome and C) an emulsion droplet.
cyclosporine A o/w emulsion for oral administration.

Pro-formulations form their nal appropriate system inside
the biological medium. Micelles loaded with cyclosporine A are
formed inside the gastrointestinal tract after the administration of
Gengraf (Abbott, Chicago, US). Emulsions can be obtained with
self-emulsifying drug delivery systems (SEDDS), such as Neoral
and Sandimmune (Novartis, Basel, Switzerland) leading to
different cyclosporine A emulsions inside the gastrointestinal
tract. Interestingly, Neoral was demonstrated to lead to a microemulsion with smaller droplet size than Sandimmune after selfemulsication, causing an increase in bioavailability of 239% and
an increased plasma peak concentration (Cmax) and area under the
curve of the plasma concentrationetime curve (AUC) when
compared to Sandimmune [84e87]. The mechanisms behind selfemulsication have been identied as follows: i) diffusion and
stranding, ii) osmotic pressure and iii) changes in the characteristics of the surrounding medium (e.g. pH or ionic strength)
[88e92].
These surfactant-related formulations require extensive characterizations (e.g. solubility of the drug, size of the micelle, liposome or droplet, viscosity, osmolarity or stability) and can be
related to the following risks: i) toxicity of the excipients (which
could represent a high percentage of the nal composition), ii) drug
precipitation and iii) modication of the pharmacokinetic prole
and biodistribution.
2.2.5. Complexation with cyclodextrins
Cyclodextrins (CDs) are a family of cyclic oligosaccharides presenting a hydrophilic surface and a hydrophobic cavity that can be
classied into a, b or g CDs according to their number of saccharide
monomers. In addition to the native non-substituted CDs, a large
variety of CD derivatives are also currently available. Fig. 6A illustrates the structure and characteristics of the four CDs included in
the US Pharmacopeia [93]. CDs are known to act as drug solubilizers
by forming dynamic inclusion complexes with poorly watersoluble drugs [94e100]. Despite the fact that the drug-CD
complexation involves non-covalent interactions, it modies the
physico-chemical properties of both the CD and the drug. Complex
formation and dissociation involve different mechanisms. Complex
formation is linked to i) hydrophobic interactions, ii) release of the

high-energy water molecules inside the CD and iii) dissolution of
the drug inside the CD cavity. While drug-CD complex dissociation
is based on the continuous dilutions and displacements that take
place in vivo, leading to an efcient release of the drug from its
complex, as shown in former investigations [95].
Besides an enhanced solubility, drug-CD complexes can lead to
an improved drug availability by acting as drug carriers, and to an
improved drug stability by preventing drug degradation
[95,99,101e105]. The carrier-like behavior of CDs is illustrated in
Fig. 6B. In addition, CDs are considered as non-toxic [103,104,106].
CD-based formulations require a comprehensive characterization regarding complex formation, stability and structure (e.g.
complex stoichiometry, stability constants).
The complexation approach was explored for the formulation of
cyclosporine A with aCD resulting in a higher penetration, higher
therapeutic effect and lower toxicity than the equivalent oily
formulation [107e109]. However, to date, there is no commercial
formulation containing cyclosporine A and CDs. In contrast, the
combination of CDs and prostaglandins (PGs) can be found in a
number of marketed formulations. For example, Caverjet Dual
(Pzer, New York, US), Prostavasin and Prostandin 500 (Ono,
Osaka, Japan) contain PGE1 and aCD for the systemic treatment of
cardiovascular-related diseases or dysfunctions. Prostarmon E
(Ono, Osaka, Japan) contains PGE2 and bCD for the induction of
uterine contractions after its oral administration.
The complexation strategy can also be combined with other
solubilizing strategies such as i) hydrophilic polymers, ii) drug salts,
iii) solid dispersion strategies or iv) cosolvents [102,110e115]. One
example is Sporanox (Janssen, New Jersey, US) which contains
HPbCD together with propylene glycol as cosolvent for the
formulation of itraconazole for the systemic treatment of fungal
infections.
The complexation strategy has been gaining interest in the past
years, in conjunction with the surge of a variety of substituted CDs.
This attractive and sophisticated technology brings new opportunities for the development and patent-protection of innovative
formulations. Nevertheless, its cost is still high due to added regulatory hurdles and the elevated cost of materials.
Fig. 6. A) Structure and characteristics of cyclodextrins (CDs) included in the US Pharmacopeia such as native aCD, bCD and gCD as well as the substituted hydroxypropylbCD
(HPbCD) [93]. B) Potential effect of the use of a CD for the formulation of a drug that has to reach a biological barrier protected by an aqueous layer (such as mucosal secretion or tear
uid). The CD interacts with the drug by: i) forming a complex, ii) caring the drug across the aqueous layer and iii) allowing drug release close to the biological barrier for its
subsequent absorption after complex dissociation. When the drug is formulated alone (upper part of the scheme), the crossing of the aqueous layer is more difcult and potentially a
lower amount of drug can reach the biological barrier for its absorption.
2.3. Administration modication

Another option to circumvent possible limitations of poorly
water-soluble drug formulations is to modify the administration
strategy. Although the oral route seems to be the golden standard
for drug administration, it presents limitations linked to drug
availability and potential systemic side effects. The use of an
alternative administration route can be particularly interesting
considering that previously mentioned physical or chemical
modications do not always allow an appropriate drug delivery.
On one hand, alternative administration routes can be used to

achieve a systemic release of a drug. Testosterone is a steroid
hormone practically insoluble in water that has a rapid hepatic
clearance, therefore requiring prolonged drug delivery systems or
frequent administration. Intramuscular depot formulations or
subcutaneous implants require invasive techniques for their
administration. The transdermal and buccal routes were explored
as alternative noninvasive options for the delivery of this drug.
The developed transdermal and buccal formulations were
demonstrated to achieve similar circulating concentrations of
Fig. 7. Pros and cons of the presented strategies for formulating and delivering poorly water-soluble drugs.
10
testosterone as the systemic options, while improving patient

comfort [116,117].
On the other hand, local administration routes can be used for
the treatment of local diseases. Indeed, local routes are the best
option for the treatment of local diseases, allowing a high ratio of
local to systemic drug concentrations which is translated into the
achievement of the pharmacological effect with minimal systemic
secondary effects. In this context, implants represent an attractive
option for the local prolonged release of drugs; their main
application elds are ophthalmology, cancer therapy and birth
control [118]. Retisert (pSivida Corporation, Watertown, US) is an
intravitreal insert delivering active concentrations of ucinolone
for up to three years allowing the treatment of chronic posterior
uveitis [119]. Gliadel (Arbor Pharmaceuticals, Atlanta, US) is an
intracerebral implant containing carmustine placed on the brain
tissue after surgical resection of the tumor for the prevention of
glioblastoma recurrence [120]. Finally, Nuvaring (Merck, New
Jersey, US) is an intravaginal implant containing estrogens for
contraceptive purposes which was demonstrated to result in a
lower estrogen exposure than with the use of other oral or
transdermal contraceptive options [121].
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
3. Conclusion
During the last decades, a number of pharmaceutical strategies
have been developed for the formulation and delivery of poorly
water-soluble drugs. In this article, eight of these strategies have
been presented and critically discussed in light of examples of
marketed products. The presented approaches included i) chemical
modications such as the adjustment of the pH and the design of
prodrugs, ii) physical modications such as the use of modied
solid states of the drug, small drug particles, cosolvents, surfactants,
lipids and cyclodextrins and iii) modications of the administration
strategy such as the use of alternative local administration approaches. These strategies can be used alone or in combination and
offer a panel of options for formulators to address the challenges
related to poorly water-soluble drugs. Pros and cons of each strategy are presented in Fig. 7.
Through this article it could be seen that the development of a
generic approach to solve drug solubility issues is not possible for
two main reasons. The rst reason is because each drug presents a
different set of specic challenges. The second reason is related to
the fact that the modication of the solubility of a drug could affect
many drug properties such as its lipophilicity, stability,
permeability, availability or elimination, which can potentially inuence its in vitro and in vivo behavior in a non-predictable manner.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
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13
J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

H. Grohganz1, K. Lbmann1, 2, P. Priemel1, 2, K. Tarp Jensen1, K. Graeser3, C. Strachan2, 4, T. Rades1*
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, DK-2100 Copenhagen , Denmark
2
School of Pharmacy, University of Otago, Dunedin, New Zealand
3
Pharma Research and Early Development, Pharmaceutical Preformulation, F. Hoffmann-La Roche Ltd., Basel, Switzerland
4
Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
*Correspondence: thomas.rades@sund.ku.dk
1
The transformation to an amorphous form is one of the most promising approaches to address the low solubility of drug compounds, the
latter being an increasing challenge in the development of new drug candidates. However, amorphous forms are high energy solids and tend to
recrystallize. New formulation principles are needed to ensure the stability of amorphous drug forms. The formation of solid dispersions is still
the most investigated approach, but additional approaches are desirable to overcome the shortcomings of solid dispersions. Spatial separation by
either coating or the use of micro-containers has shown potential to prevent or delay recrystallization. Another recent approach is the formation
of co-amorphous mixtures between either two drugs or one drug and one low molecular weight excipient. Molecular interactions between the
two molecules provide an energy barrier that has to be overcome before single molecules are available for the formation of crystal nuclei, thus
stabilizing the amorphous form.
Key words: Amorphous Solid dispersion Glass solution Spatial separation Co-amorphous.
In the pharmaceutical industry, poor physicochemical properties

of potential new drug candidates such as low solubility, pose a challenge when turning a promising molecule into a successful drug. Low
or erratic bioavailability can have its cause in low solubility or slow
dissolution and therefore great efforts are taken in order to improve the
solubility and subsequently the bioavailability of promising molecules.
One approach has been to convert crystalline drug material into
amorphous form. There are various techniques available to produce
amorphous form such as spray-drying or freeze-drying, grinding,
melt-extrusion or melt-quenching, and co-precipitation. Especially
in the industry, techniques such as spray-drying and melt extrusion
are commonly used to prepare amorphous material.
A molecule in an amorphous form is in a higher energy state
compared to its crystalline counterpart. Due to the increased mobility
within the system, amorphous compounds exhibit a higher solubility
which in turn may lead to a higher saturation concentration, thereby
increasing the overall dissolution rate [1]. However, despite these
theoretical expectations, there are limitations when working with an
amorphous form. In the following sections, the solubility advantage,
an overview on prediction of physical stability and a discussion on
the existence of the amorphous state will be briefly highlighted,
followed by recent trends to improve the quality of amorphous drug
formulations.
The advantages of an amorphous drug form are to reach a higher
solubility, create a supersaturated solution and effectively reach a
higher bioavailability compared to its crystalline counterpart, due to the
absence of a crystal lattice. In reality however, the expected behaviour
is often difficult to observe [2], due to difficulties in determining the
solubility of amorphous materials under true equilibrium conditions.
When introducing an amorphous compound into an aqueous environment, there is an increased probability of recrystallisation, either
directly from the amorphous material or through crystalline precipitation from the supersaturated solution. In recent reviews, practical
issues of determining the actual advantages of using the amorphous
state are discussed [3, 4].
Moisture acts as a plasticiser for amorphous compounds, reducing
its glass transition temperature (Tg) and therefore enhancing recrystallisation, not only in direct contact with water, but also during storage
through water in the gas phase. The physical stability and especially,
the prediction thereof, is to date still an area of increased research
as currently no method exists, to predict a priori the stability of an
amorphous compound.
Amorphous material above the Tg tends to crystallize fast, as
sufficient mobility exists within the system to allow for nucleation
and crystallisation of the material. It has long been hypothesised that
the amorphous state below Tg does not possess sufficient mobility to
allow for recrystallization, and it was proposed to store amorphous
materials 50 K below its Tg to ensure stability [5]. However, this
rule of thumb has been shown not to hold true as crystallisation
was observed at temperatures well below Tg-50K [6].
I. Prediction of amorphous stability
Ways of stabilising the amorphous state against recrystallisation and

the prediction thereof has been at the centre of amorphous research in
the past decades. As the glassy state is a non-equilibrium state, simple
extrapolation from the stability under accelerated conditions based on
the Arrhenius relationship do not apply, and real time storage experiments are currently the only way to confidently predict the stability
of an amorphous form. Over the years, researchers have focused on
correlating the stability from easily accessible measurements, thereby
concentrating on thermodynamic factors, such as enthalpy and entropy,
and on kinetic factors, such as the molecular mobility.
Molecular mobility can be expressed as its reciprocal, the relaxation time, . Techniques like dielectric spectroscopy and solid state
NMR can measure the relaxation of a sample directly, however, these
techniques are not commonly available in every laboratory setting and
measurements can be time consuming. A theoretical approach uses
molecular dynamics simulations [7]. The mobility can also be indirectly assessed by using differential scanning calorimetry data (DSC)
[8] and empirical approaches such as the Kohlrausch-Williams-Watts
(KWW), Adam-Gibbs (AG) and the Vogel-Tammann-Fulcher (VTF)
equations [9]. The calculated mobility is then correlated to observed
physical stability, however the actual information content is limited,
as only 2-3 drugs were actually used in these case study approaches.
An excellent review on this topic has been published by Bhugra et al.
[10].
403
14

H. Grohganz, K. Lbmann, P. Priemel, K. Tarp Jensen, K. Graeser, C. Strachan, T. Rades
Results showed that no simple method exists to easily correlate

physical stability below the Tg with either molecular mobility or
thermodynamic parameters for a larger set of drugs. This approach
was refined by Baird et al. who used a set of 51 molecules and classified them according to their recrystallization tendency into 3 classes.
Analyses of properties of the individual classes seemed to provide
promising results [12].
Despite the unsatisfying results in correlating the physical stability of a number of different drugs with molecular mobility, it was
observed that the relaxation time calculated by the KWW and the
AG equations, could be used to rank the stability of two differently
prepared amorphous forms of simvastatin [13]. These findings were
followed up and confirmed for three differently prepared amorphous
forms of indomethacin [14]. It was proposed that this method could
be suitable to select the preparation technique that would give the
most stable amorphous form for a given drug.
Despite past research, the amorphous state is still not completely
understood, and in the past only few amorphous products have been
marketed. In the pharmaceutical industry, an amorphous form is
rarely used on its own but rather formulated as a solid dispersion to
enhance the stability. A new method has been introduced to prepare
the amorphous state: the microprecipitated bulk powder technology
(MBP) where the amorphous state is co-precipitated with a polymeric
carrier to form an amorphous solid dispersion [15]. Recently the FDA
approved a new anti-cancer drug from Roche, formulated as a solid
dispersion using the novel MBP technology (Zelboraf).
Figure 1 - Percentage amorphous content and relaxation time after

30 days of storage at Tg - 20 C. (red triangles) Relaxation time, (grey
bars) amorphous content. Error bars for the relaxation time lie within
the symbol. Figure reproduced from [11] with permission from Elsevier.
Graeser et al. published for the first time an approach where

thermodynamic parameters as well as the molecular mobility were
assessed and compared to the observed physical stability of a test set
of 12 drugs (Figure 1) [11].
A modified version of the AG equation was used to calculate
from DSC data, and DSC data was also used to calculate the differences in thermodynamic properties between the crystalline and the
amorphous state (configurational properties). These configurational
properties are strictly speaking only valid above the Tg, i.e. in the
equilibrium supercooled melt state and the configurational entropy
showed some correlation with the stability above the Tg (Figure 2).
II. The influence of process parameters
As stated above, the amorphous state can be produced by different

techniques and the most common technique in the previous studies
has been via the melt-quenching route. However, molecules that are
thermo labile are often spray-dried or milled. Hence, the question
arises, whether the manufacturing technique has an influence on the
properties and stability behaviour of the amorphous state [16-18].
The influence of the preparation technique and parameter settings
on the resulting amorphous state starting from both -form and -form
of indomethacin was investigated [19]. Using XRPD and Raman
spectroscopy in combination with multivariate analysis, differences
between the differently prepared amorphous forms on a molecular
level could be detected (Figure 3).
These molecular differences were related in differences in the physical stability during storage in the rank order of stability cryo-milled
() = ball milled () < ball milled () < spray-dried < cryo-milled ()
< quench cooled. This ranking did not linearly correlate with the differences in molecular structure, and the authors indicated that these
structural variations may not directly affect physical stability.
Figure 2 - (a) Configurational entropy and enthalpy vs. stability of the

drugs above Tg. (b) Configurational Gibbs free energy vs. stability.
Stability was assessed by relating the recrystallization temperature to
the glass transition and melting temperature via the reduced recrystallization temperature [(Tc - Tg)/(Tm - Tg)]. Figure reproduced from [11]
with permission from Elsevier.
Figure 3 - X-ray diffractograms of freshly prepared amorphous forms

of indomethacin prepared by different preparative techniques. Figure
reproduced from [19] with permission from Elsevier.
404
15

Taking the same preparation method but varying the parameters,

such as decreasing the cooling rates for QC material and prolonging
the milling time also led to X-ray amorphous material with different
quality. It was concluded that also different parameter settings within
the same technique will result in different amorphous states.
The differences in cooling rate were detectable on a molecular
level; however, the dissolution behaviour was not affected. For the
milled material however, differences in the dissolution were observed
for the amorphous material and an increase compared to the crystalline material was only observed after exceeding a critical minimum
milling time [19, 20].
III. Amorphous drug formulations
The stabilisation of amorphous drugs is usually achieved by addition

of a second substance. The approaches can be grouped depending whether
the other compound is or is not interacting on a molecular level with
the drug, and whether the substance is a polymer or a small molecule.
With larger polymers, usually glass solutions are formed, where the
drug substance is dissolved molecularly in the polymer or vice versa.
At the University of Copenhagen two newer approaches are currently
in the focus of investigation. Spatial separation is an approach where
the second substance is in contact with the drug on a particular level,
i.e. surrounded by microcontainer walls or by coatings of particles. The
other approach is the formation of co-amorphous mixtures where the
drug is stabilised via molecular interaction with another small molecule.
Figure 4 - Crystalline content of amorphous indomethacin stored in

microcontainers (174 and 223 m) and in bulk phase at 23% RH. Figure
reproduced from Nielsen et al., 2012 with permission from Elsevier.
2. Spatial separation
Another recent approach is to stabilise amorphous materials via

spatial separation [35]. Indomethacin (IMC) was transformed to the
amorphous form by quench cooling it into micro-containers (73, 174
and 223 m diameter). Those were stored at 23% RH and the physical
stability of amorphous IMC was monitored with Raman spectroscopy
and compared to bulk amorphous IMC. While around 50% of the bulk
material crystallised to the form after 5 days, the 174 m microcontainers showed around 15% and the 223 m microcontainers around
25% of crystallinity (see Figure 4). However, the 73 m containers
recrystallised fast to the form which would be expected for storage
condition above 42% RH [36]. This observation was explained with
the container material possibly absorbing water vapour or capillary
condensation, both explanations would lead to a higher humidity in
the direct environment of the amorphous IMC, hence resulting in the
form.
Applying a coat on the surface of amorphous particles is another
way of spatial separation. Amorphous IMC particles were coated with
gold using a sputter coater or with polyelectrolytes via electrostatic
assembly [37]. The physical barrier around the particles improved
their physical stability by reducing surface mobility, and crystallites
already existing before the coating process did not grow upon further
storage [37]. Similarly, griseofulvin [38] and nifedipine [39] which
both undergo surface crystallisation, showed reduced recrystallisation
after a gold film was applied. Spatial separation/reduction of molecular
mobility on the surface requires no functional groups such as H-bond
acceptors and/or donors for stabilisation of amorphous drugs and
should therefore be generally applicable to a broader range of drugs.
However, it was also shown that the substance applied as coat also
influences the physical stability of amorphous celecoxib (inulin <
PVA ~ PVAP) [40]. DSC studies provided evidence for drug polymer
mixing at the interface, hence stabilisation might be further improved
through drug-polymer interactions in this case.
1. Glass solutions and solid dispersions
Glass solutions are the most established systems to improve solubility and stabilize amorphous drugs [21-23]. Usually they consist of
a drug and a polymer, often polyvinylpyrrolidone (PVP), polyvinylalcohol, cellulose derivates or polyethyleneglycole (PEG) and they
can be prepared through melt quenching, ball milling, spray drying
or hot melt extrusion [24]. Analytically the existence of a single glass
transition temperature as well as peak shifts in infrared and Raman
spectroscopy due to interactions are taken as indicator for the successful formation of a glass solution [25, 26]. However, it was shown
that amorphous felodipine PVP solid dispersions with different PVP
contents consisted of nano-domains of drug and polymer rather than
being a molecularly dispersed system [27]. In another study a solid
dispersion of a drug and PVP/VA was prepared via hot melt extrusion
with two different sets of processing parameters [28]. While the data
of freshly prepared samples differed neither in DSC nor XRPD, one
sample already started to recrystallize after two months while the other
was still amorphous. Raman microscopy revealed differences in the
drug distribution in the less stable sample being less homogeneous.
But even in a formulation with drug molecularly dissolved into the
polymer, phase separation may occur during storage, especially when
stored at high temperature and/or humidity. The strength of drug
polymer interaction, hygroscopicity and API hydrophobicity were
found to influence phase separation [29].
To be able to predict if a glass solution of a certain drug polymer pair
would be successful and if phase separation would be likely to occur,
the solubility/miscibility of drug and polymer were considered. The
solubility parameters [30] and the Flory Huggins interaction parameter
[31] have been calculated and good correlation to experimental data
was found. In another approach [32] pair distribution functions (PDF)
of single components and the drug (or sugar) polymer mixtures were
compared to each other and differences were attributed to a glass solution formation and confirmed with DSC data (single Tg or two Tgs).
The improved physical stability has not yet been clearly linked to a
stabilisation mechanism, but is probably a complex result of several
factors. In literature the increase of the Tg, antiplastisation, decreased
molecular mobility of the drug molecules by the polymer chains [33],
intermolecular interactions [34], type and ratio of polymer have been
discussed as the main stabilising factors.
3. Co-amorphous drug formulations
In the past few years interest towards the use of amorphous multicomponent mixtures comprising only molecules with a low molecular
weight, instead of the use of large polymers, has increased. The use
of small molecules, such as urea, citric acid, sugars and nicotinamide,
as excipients in binary amorphous blends has been reported [41-44].
A stabilization effect of anhydrous citric acid on the amorphous form
of paracetamol in binary mixtures was observed. The reason for the
increased stability could be later assigned to hydrogen bonding between
paracetamol and citric acid [45].
To further explore this approach using low molecular weight components, Chieng et al. developed co-amorphous drug/drug mixtures.
405
16

The idea behind these systems was first, to create stable amorphous
systems without the use of polymers, and second, developing new
formulations of two drug candidates that could be used in combination
therapy [46], for example a pharmacological relevant pair of drugs. In
addition, the term co-amorphous was introduced for the first time
to differentiate amorphous blends comprising only low molecular
weight components to amorphous drug-polymer mixtures, which are
generally referred to as solid dispersions or glass solutions. In their
study, co-amorphous mixtures of indomethacin (IND) and ranitidine
hydrochloride (RAN) in weight ratios of 2:1, 1:1 and 1:2 were produced
by vibrational ball milling. They could show that the pure drugs alone
were poor glass formers, i.e. it was not possible to transform them into
the amorphous state under similar milling conditions. This changed
drastically when mixtures of two components were processed. Fully
co-amorphous blends were obtained and showed high physical stability
against crystallization. Interestingly, the order of physical stability did
not follow the order of increasing Tg as initially expected, but could
be addressed to molecular interactions between IND and RAN at
molecular and bulk level. These interactions were most distinctive in
the co-amorphous 1:1 mixture. Thus, the 1:1 blend was more stable
than the co-amorphous mixtures at 2:1 and 1:2 even though it had an
intermediate Tg to those of the 2:1 and 1:2 mixtures. However, this
finding could not be related to specific interactions in a 1:1 molar ratio
since weight ratios were used in the study.
In order to further study stability benefits of the 1:1 mixtures
and potential molecular interactions, Alles et. al. investigated coamorphous mixtures of naproxen (NAP) and cimetidine (CIM) at molar
ratios instead of weight ratios [47]. Indeed, the co-amorphous blend at
the molar ratio 1:1 again showed the highest physical stability in spite
of its Tg being in between those of the co-amorphous mixtures at 2:1
and 1:2. The 1:1 blend remained amorphous up to approx. six month
whereas the other mixtures showed recrystallization of the excess
component (Figure 5). In addition, the 1:1 co-amorphous mixture
showed a four-fold and two-fold increase in the intrinsic dissolution
rate of naproxen and cimetidine, respectively, compared to the pure
crystalline compounds. Furthermore, the drugs were released in a
synchronized 1:1 molar fashion which means that with every NAP
molecule one CIM molecule is released into the dissolution medium.
These findings were explained by specific interactions between NAP
and CIM in a pair-wise 1:1 molar fashion.
The concept of co-amorphous drug/drug formulations was further
investigated with respect to the factors influencing dissolution and
stability in studies on co-amorphous IND/NAP [48] and glipizide
(GPZ)/simvastatin (SVS) [49]. In the study on IND and NAP, we

were able to confirm the result from the previous studies with respect
to a synchronized release of the 1:1 molar blend and recrystallization
of the excess component in the 1:2 and 2:1 molar ratios whereas the
1:1 ratio samples remained amorphous, even though the 1:1 molar
ratio had an intermediate Tg to the 2:1 and 1:2 ratio mixtures. It was
possible to show specific molecular interactions between the two
drugs IND and NAP at the 1:1 molar ratio. In particular, the creation
of a heterodimer between both drugs could be confirmed using FTIR
spectroscopy and density functional theory (DFT) calculations [50].
The specific hydrogen bonds between IND and NAP stabilized the
co-amorphous 1:1 blend (heterodimers). In order to convert back to
the respective individual crystalline drugs, it would be necessary to
break the hydrogen bond in the heterodimer, followed by reorientation of two like-molecules to form a homodimer. These homodimers
would then be able to create crystal nuclei, which are the starting
points for crystal growth. In this respect, the 2:1 and 1:2 mixtures
contain two species of dimers, heterodimers between IND and NAP
and homodimers between the molecules of the excess component.
These homodimers are readily able to recrystallize. Therefore, the 1:1
molar ratio showed the highest physical stability among the mixtures
investigated. It was concluded that specific molecular interactions
between components in a co-amorphous formulation can offer the
basis for an intrinsic resistance towards recrystallization. Overall, it
was concluded that intermolecular interactions play a crucial role in
co-amorphous formulations and have a high impact on the physical
stability regardless the Tg.
The study on co-amorphous mixtures between SVS and GPZ was
special, in the sense that the blends were homogeneous one phase
systems but did not show any signs of intermolecular interactions
[49]. The dissolution of these mixtures revealed no advantage over
that of the pure amorphous drugs. However, the storage stability of
the co-amorphous mixtures was increased compared to the individual
amorphous drugs and amorphous physical mixtures. It could be shown
that molecular level mixing present in co-amorphous systems positively
affected physical stability.
Since not every drug has a suitable partner drug for combination therapy, there was a strong need to extend this approach to coamorphous mixtures comprising a drug and low molecular weight
excipients. Amino acids exist in the biological receptor of drugs and
those amino acids that are binding to the drug at the active site consequently interact strongly with drugs in vivo. Lbmann et al. [51,
52] introduced a strategy in which receptor amino acids relevant for a
drug were chosen in order to create a physically stable co-amorphous
systems (Figure 6). Co-amorphous blends were prepared by ball
Figure 5 - XRPD patterns of physical stability study at various storage

temperatures of co-amorphous NAP-CIM at the molar ratios 2:1, 1:1
and 1:2 showing the recrystallization of the excess component after
33 days. Figure reproduced from Alles et al., 2009, with permission
from Elsevier.
Figure 6 - Schematic depiction of the research strategy using amino

acids as co-amorphous excipients: a. find the active receptor site of a
given drug (adapted from [53]), b. choose the drug binding amino acids,
c. prepare a co-amorphous formulation, d. intrinsic dissolution testing.
406
17

milling and contained either of the two drugs carbamazepine (CBZ)

and IND in a combination with a corresponding receptor amino acid,
i.e. phenylalanine (PHE)/ tryptophan (TRP)[53] and arginine (ARG)/
tyrosine (TYR)[54], respectively.
It was possible to obtain homogeneous co-amorphous blends at a
1:1 molar ratio containing either one of the two drugs and the amino
acids ARG, PHE and TRP. The dissolution rate of these mixtures was
increased over the respective crystalline and amorphous pure drugs and
the co-amorphous formulations showed excellent physically stability.
The improved physical stability could be explained by markedly higher
Tgs compared to the individual drugs and molecular level mixing
with the amino acids. Studying interactions revealed that in all of the
co-amorphous mixtures with CBZ, both H-bonding and - interactions could be identified. It could be shown that interactions play a
crucial role in the physical stability of co-amorphous mixtures as the
co-amorphous mixtures with molecular interactions in this study also
show the best physical stability kinetics.
Overall molecular interactions between drug and amino acids
were only identified in those co-amorphous mixtures that included
at least one amino acid from the biological target site as initially
anticipated. However, the interactions included the side chains, the
carboxylic acid and amino functional groups of the amino acids which
are involved in the peptide bond in the backbone of the protein and
thus not available for specific interactions with the drug target at the
biological active site. Therefore, a direct connection between the
interactions occurring between the drugs and the amino acids in the
co-amorphous mixtures and the biological targets could not be made.
Formulating co-amorphous blends with a drug and amino acids from
the natural binding site, however, can give a good starting point in
choosing potential amino acids for a co-amorphous formulation. In
order to identify the most advantageous amorphous drug formulations
the choice of amino acids as excipients should be based on an assessment of Tg, molecular interactions as well as molecular level mixing.
Amino acids were shown to be a promising alternative to solid
dispersions of drug in polymers. The use of small molecular amino
acids has a potential in reducing the bulk volume compared to formulations based on solid dispersions, as large quantities of polymer
are required to create a solid solution. Furthermore, limited solubility
of some drugs in the polymers as well as high risk of recrystallization due to hygroscopicity of most polymers are challenges, which
co-amorphous formulations including amino acids could overcome.
In addition, amino acids are non-toxic and generally regarded as
safe. All together amino acids have a potential to form the basis for a
new platform technique to overcome challenges associated with the
amorphous state of poorly soluble drugs.
gaining attention. Here suitable processes that enable the formation

of a coat without triggering recrystallisation of the drug will need
to be investigated in future. Last but not least, the concept of coamorphous mixtures is a new rationale for the stabilisation of amorphous compounds, mostly based on molecular interactions with other
small molecular compounds. New methods to produce co-amorphous
mixtures in industrial scale and the way to find or design the optimal
excipient for each specific drug need to be investigated to reach the
full potential of this approach.
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Manuscript
Received 7 March 2013, accepted for publication 30 March 2013.
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20

N. Thomas, T. Rades, A. Mllertz*
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, DK-2100 Copenhagen , Denmark
*Correspondence: anette.mullertz@sund.ku.dk
The increasing number of poorly water-soluble drugs in development in the pharmaceutical industry has sparked interest in novel drug delivery
options such as lipid-based drug delivery systems (LbDDS). Several LbDDS have been marketed successfully and have shown superior and more
reliable bioavailability compared to conventional formulations. However, some reluctance in the broader application of LbDDS still appears,
despite the growing commercial interest in lipids as a drug delivery platform. This reluctance might at least in part be related to the complexity
associated with the development and characterization of LbDDS. In particular, the lack of standardized test protocols can be identified as the
major obstacles for the broader application of LbDDS. This review seeks to summarize recent approaches in the field of lipid-based drug delivery
that try to elucidate some critical steps in their development and characterization.
Key words: Lipids (super-)SNEDDS In vitro lipolysis Absorption.
The oral route is considered the preferred way of drug administration

since it has proven to be convenient and acceptable for the majority of
patients [1]. Moreover, oral dosage forms are relatively easy to manufacture at comparably low costs, making them an attractive delivery
form for the pharmaceutical industry [2]. However, conventional oral
delivery is currently facing challenges by an increasing number of poorly
water-soluble drugs demonstrating poor and variable absorption. The
unmet need for reliable and reproducible absorption of many poorly
water-soluble compounds has stimulated formulation scientists to utilize
enabling drug delivery systems that differ greatly from conventional
delivery systems [3]. Amongst other approaches the utilization of lipidbased drug delivery systems (LbDDS) has attracted particular interest,
not only in academia but also in pharmaceutical industry, as indicated
by the number of LbDDS approved for the market (TableI). However,
the number of commercially available LbDDS is still limited indicating that their full potential still remains to be explored. Most likely
the reluctance of the pharmaceutical industry to develop LbDDS as a
platform delivery system for (lipophilic) poorly water-soluble drugs
is at least in part due to the complexity of LbDDS and the current
lack of in vitro protocols predictive for the performance of LbDDS
in vivo. On the other hand there are also economical considerations
such as greater cost of goods for the development and formulation of
LbDDS compared to conventional solid dosage forms. As the majority of LbDDS are liquids, their manufacturing requires expertise in
hard-gelatine capsule filling or soft-gel encapsulation technology
which might not be readily available in-house [3, 4]. Furthermore,
compared to solid dosage forms, the existence of the drug dissolved in
a LbDDS poses a potential disadvantage with regard to the chemical
stability and shelf-life for the intended drug product [5, 6].
The current work reviews the possibilities and limitations of LbDDS
to improve the bioavailability of lipophilic drugs and describes the
challenges and caveats in the development and in vitro characterization of LbDDS, highlighting the importance to identify the solid state
properties of drug precipitating during in vitro lipolysis. Together with
the evaluation of different animal models used during recent in vivo
studies this review aims at the better understanding of LbDDS for a
broader application of these promising delivery systems.
Table I - Examples of marketed LbDDS and their composition (adapted

from reference [7]).
Drug
Trade
name
Lipid components
Surfactants
Hydrophilic
cosolvents
Alfacalcidol
One-Alpha
Sesame oil
Amprenavir
Agenerase
TPGS
PEG 400,
PG
Ciprofloxacin
Cipro
Mediumchain TAG,
lecithin
Tween 20
Clomethiazole
edisilate
Heminevrin
Fractionated TAG
of coconut
oil
Cyclosporin A
Neoral
MAG, DAG
and TAG of
corn oil
Cremophor
RH 40
Ethanol,
glycerol,
PG
Cyclosporin A
Sandimmune
Corn oil
Labrafil M2125CS
Ethanol,
glycerol
Dronabinol
Marinol
Sesame oil
Fenofibrate
Fenogal
Gelucire
44/14
Lopinavir/
ritonavir
Kaletra
Cremophor
RH 40
Ethanol,
glycerin,
PG
Ritonavir
Norvir
Oleic acid
Cremophor
EL
Ethanol
Saquinavir
Fortovase
Mediumchain MAG
and DAG
Abbreviations: TPGS, tocopherol polyethylene glycosuccinate; PEG,

polyethylene glycol; PG, propylene glycol; TAG, triacylglyceride; MAG,
2-monoacylglyceride; DAG, diacylglyceride.
are associated with poor and variable absorption [8, 9]. Moreover,
the absorption of poorly water-soluble drugs is often affected by the
consumption of food [10]. In many cases absorption of poorly watersoluble drugs is facilitated by the presence of food. Lipids, in particular,
have been recognized to play a profound role in the solubilization and
absorption of lipophilic drugs. In an attempt to harness the beneficial
I. The role of lipids in drug delivery
Sufficient aqueous solubility along with good intestinal permeability is crucial for adequate drug absorption, ultimately leading to
sufficient bioavailability [8]. Conversely, poorly water-soluble drugs
375
21

effects of lipids on drug absorption, research on LbDDS has become

increasingly popular as a potential platform for the delivery of poorly
water-soluble, lipophilic drugs [5, 7, 10, 11].
LbDDS include simple lipid solutions, liposomes, micellar solutions and more complex delivery systems such as self-emulsifying drug
delivery systems (SEDDS) and self-nanoemulsifying drug delivery
systems (SNEDDS). The common theme of these formulations is
that a co-administered drug is presented in a dissolved state, thereby
avoiding the critical dissolution step necessary for crystalline, poorly
water-soluble drugs. While simple LbDDS may only comprise of a
single lipid, SEDDS and SNEDDS typically contain four and more
excipients (lipid, surfactant, co-surfactant, and cosolvent) forming
anhydrous isotropic pre-concentrates. Following gentle agitation in
aqueous medium the pre-concentrates generate kinetically stable emulsions (SEDDS, particle size 0.2-2 m) or nano-emulsions (SNEDDS,
particle size < 0.2 m). In this context it should be mentioned that the
term SNEDDS is preferred over SMEDDS (self-microemulsifying
drug delivery systems) since the latter term should be reserved for
thermodynamically stable systems [12, 13]. The rather loose use of
the terminology might be attributed to the macroscopically similar
emulsification process and the translucent to opaque appearance of
the dispersions owing to their submicron particle sizes.
In contrast to conventional excipients used for oral solid dosage
forms, lipid excipients are susceptible to digestion in the gastrointestinal tract. In fact, digestion can be described as the first step after
administration and dispersion of the LbDDS in a series of complex
events often resulting in improved drug solubilization by colloidal
structures such as vesicles and mixed micelles [14, 15].
Digestion of triacylglycerols (derived either from LbDDS or food)
is initiated in the stomach by the hydrolytic activity of gastric lipase
and contributes to approximately 10-20% of the total lipolysis [16].
The surface active digestion products (diglycerides, partially ionized
fatty acids) and the grinding forces of the stomach support the initial,
crude emulsification of the chyme which subsequently empties into the
duodenum. The following hydrolysis of the lipids by the concerted action of pancreatic lipase, co-lipase and bile salts finalizes the enzymatic
breakdown of the lipids, generating two moles of fatty acids and one
mole of 2-monoglycerides for each mole triacylglyceride (Figure1).
Many physiological and biochemical reactions of the digestion
process have been described in great detail [18-21]. Rather simple
oil emulsions were used in these pioneering studies compared to the
complex LbDDS commonly employed for recent pharmaceutical
applications. Nevertheless, the early investigations on lipid digestion provided important information such as that the digestion of fat
emulsions depends on their initial physico-chemical properties (e.g.
faster digestion of fine emulsions with smaller droplet size compared
to coarse emulsions) providing the bases for later, pharmaceutical
studies [22]. However, there is still a considerable lack in the understanding of how the digestion products interact with drugs leading to
enhanced absorption. Many of the current approaches to understand
drug absorption are concerned with the importance of drug solubilization in different biorelevant media using various levels of bile salt
and phospholipids [23, 24]. While this approach appears feasible for
the assessment of those drugs whose solubilities solely depend on the
overall concentration of surfactant, the type of surfactant and the presence of digestion products can cause considerable deviation from the
solubilities for other drugs [25-27]. As an example, danazol solubility
in biorelevant media was not affected by the type of surfactant used,
whereas fenofibrate and cinnarizine showed a substantial increase in
their solubility in media supplemented with oleic acid/monoolein as
model digestion products [27].
In addition to solubilization, several other effects of lipid excipients
in LbDDS may contribute to enhanced drug absorption. For example
highly lipophilic compounds will be directed towards the lymphatic
route when administered with long-chain lipids [28, 29]. In particular,
drugs that demonstrate pharmacological action in the lymphatic system
might benefit from this route, as well as compounds susceptible to a
high first pass metabolism [30, 31].
Moreover, the drug permeability can be elevated by LbDDS and
their digestion products by the opening of tight junctions, inhibitory
effects on efflux transporters and modulation of metabolic enzymes
[30, 32, 33]. As an example, Risovic et al. found that glyceryl monooleate decreased the expression of P-gp protein and stimulated the
intestinal lymphatic uptake of amphotericin B resulting in increased
drug absorption [32].
The presence of lipids can also prolong the residence time of
undissolved drug, for example from normal tablet formulations, in
the gastrointestinal tract, which allows for a longer time for a drug
to dissolve. It has been shown that relatively small amounts of lipids
administered as LbDDS can induce effects comparable to those observed with dietary lipids [34]. Whilst complete dissolution is desirable
for conventional formulations and compounds for which absorption
is limited by dissolution, it is not relevant for LbDDS since the drug
is usually already presented in a dissolved state. However, the importance of presenting the drug in a dissolved state requires further
investigation in light of a recent study that found the same bioavailability of danazol administered either as a solution or as a suspension
administered in the same lipid vehicle [35]. This data demonstrates
that the absence of a dissolution step alone cannot account for the
biopharmaceutical advantages of LbDDS, but that drug dissolution
(in case of a suspension), solubilization and absorption from LbDDS
are highly dynamic and complex. In fact, the underlying mechanisms
determining the absorption of a co-administered drug from LbDDS
are still not completely understood. However, several steps have been
proposed to attain successful drug absorption.
It is necessary that the drug is released from the formulation before
it can be absorbed in the small intestine as neither micelles nor oil
droplets can be absorbed intact through the intestinal epithelium [36].
According to this model, drug release from LbDDS can proceed in
two ways:
- the drug partitions directly from the formulation into the bulk (i.e.
as free drug or solubilized in bile salt micelles) and subsequently into
the enterocyte, or the drug is released from the formulation into the
bulk upon the degradation of the formulation [11]. The first pathway
has also been termed interfacial partition and can be considered
as the only release mechanism for formulations devoid of digestible
excipients [37, 38];
- the second pathway is restricted to formulations containing digestible
excipients. These can be enzymatically degraded by pancreatic lipase
and co-lipase, or other pancreatic esterases [7, 39]. The presence of
exogenous lipids further stimulates the contraction of the gall bladder releasing bile salts and lecithin into the intestine. Together with
Figure 1 - Illustration of pancreatic lipolysis at the lipid/water interface.

The lipolytic activity of the pancreatic lipase alone (i) is largely decreased
compared to the pancreatic lipase/co-lipase complex (ii). The structure
of some surfactants and the accumulation of digestion products at the
substrate surface inhibit the activity of the pancreatic lipase/co-lipase
complex (iii). Orogenic displacement of these amphiphiles by bile salts
re-establishes the activity of the pancreatic lipase/co-lipase complex (iv).
Moreover, bile salts solubilize the digestion products by incorporation
in mixed micelles and vesicles making them available for absorption
through the intestinal wall (v). Reprinted from reference [17] with permission of Elsevier.
376
22

these endogenous solubilizing agents the degradation products of

the formulation (fatty acids and 2-monoglycerides) produce a range
of colloidal species [40-42] which may have a positive or negative
influence on the solubilization capacity for the administered drug,
depending on the nature of the drug, the LbDDS and the time course
of digestion [35, 43-46].
Table II - Examples of frequently used excipients for the formulation of

lipid-based drug delivery systems. Adapted from reference [47].
II. Development of lipid-based drug

delivery systems
The vast number of commercially available excipients (TableII)

gives rise to a plethora of possible combinations for LbDDS [47].
It is perhaps due to this variety that the attempts for a classification
system for LbDDS have not been able to fully accommodate their
different physicochemical characteristics that could serve as a guide
for formulation scientists [7, 48]. Only a few structured guidelines for
the adequate selection of LbDDS for poorly water-soluble drugs have
been proposed to date [4, 49]. However, the development of LbDDS
is still largely a process driven by empirics rather than rational decision making. The proposed guidelines for the development of LbDDS
start with the solubility assessment of a drug in a range of excipients
and mixtures thereof. This is accompanied by the determination of
pseudo-ternary phase diagrams to identify areas of mutual miscibility of selected excipients and areas of self-emulsification in case a
self-emulsifying LbDDS is intended. Since the presence of drug can
alter the emulsification process the drug should be already included
in these initial studies [45].
The perspective for the successful formulation of a poorly watersoluble drug in a LbDDS is promising for drug candidates limited
by solubility and dissolution rate rather than permeability, i.e. drugs
belonging to Class 2 (poor solubility/good intestinal permeability)
according to the Biopharmaceutics Classification System (BCS) [50].
However, it would be erroneous to expect all poorly water-soluble
drugs respond equally well to the formulation as LbDDS. In fact,
for drugs demonstrating a high degree of crystallinity, formulation
as LbDDS is likely to fail if the drug is not lipophilic, as reflected by
a low solubility in triglycerides and a low partition coefficient (logP
< 2) [48]. Alternative formulation approaches for these hydrophobic
drugs are reviewed elsewhere and include salt formation, particle size
reduction, formulation as solid dispersions, and the use of cyclodextrins
[8, 49, 51, 52]. In contrast, LbDDS are a likely formulation option for
lipophilic compounds with logP > 4 and appropriate solubility of the
drug in triglycerides [48]. If necessary, the drugs solubility in LbDDS
can be improved by the inclusion of surfactants, mixed glycerides, and
cosolvents [7, 48]. It should be noted that the commonly used logP
as an estimate for lipophilicity varies with pH for ionizable drugs. In
order to account for this pH-dependency the distribution coefficient
(logD) should be assessed for weak acids and bases at different pH
values. As an example, the logD of the antimalarial drug halofantrine
(a weak base) increased by three units when the pH was changed
from pH 2 to 7 [53]. Importantly, the bioavailability of very lipophilic
compounds (logP > 6) with a solubility in triglycerides greater than
50 mg/g can increase substantially by stimulation of the lymphatic
absorption pathway, particularly when long-chain lipids are employed
containing fatty acids with more than twelve carbons [53, 54].
The characterization techniques employed following the dispersion of the pre-concentrates in a dissolution paddle apparatus or
simple magnetic stirrer include nephelometry [55], photon correlation
spectroscopy [6, 38, 56], electron microscopy [40, 45, 57, 58], and
recently, ultrasonic resonator technology [13, 59]. While the selection
of SNEDDS is often based on a good dispersion performance (indicated
by small polydispersity index and particle size) it is interesting to note
that only few studies have found evidence that finely dispersing LbDDS
are associated with improved performance in vivo [58, 60, 61].
The conventional screening of SNEDDS involves time consuming preparation and analyses of a considerable number of samples.
Water-insoluble excipients
Surfactants
Cosolvents
Beeswax
Corn oil
Glyceryl
monooleate
Ethanol
Oleic acid
Olive oil
Polyoxyl 35
castor oil
Glycerin
Soy fatty acid
Peanut oil
Polyoxyl 40
hydrogenated
castor oil
PEG 300
d--tocopherol
(vitamin E)
Rapeseed oil
PEG 400
caprylic/capric
glycerides
PEG 400
Corn oil mono-ditriglycerides
Sesame oil
Polysorbate 20
Propylene
glycol
Medium chain
(C8/C10) monoand di-glycerides
Soybean oil
Polysorbate 80
Propylene glycol
esters of fatty
acids
Hydrogenated
soybean oil
d--tocopheryl
polyethylene
glycol succinate (TPGS)
Caprylic/Capric
triglycerides
derived from coconut oil or palm
seed oil
Cottonseed oil
Sorbitan
monolaurate
Recently, design of experiments and response surface modeling has

been utilized to optimize the screening process [62-64]. Apart from
reducing the work load this approach also allowed the investigation of
the impact of the individual excipient on the dispersion characteristics
[64]. Further work is required to elucidate whether the currently used
responses (particle size, solubility) employed in these models are in
fact suitable for the optimization of LbDDS, considering that these
delivery systems are susceptible to digestion inevitably changing the
initial properties of the formulation.
III. In vitro characterization

of lipid-based drug delivery systems
In vitro lipolysis is an important technique employed to mimic

the digestion of food and formulation derived lipids such as those
contained in LbDDS [65]. Although the protocols for in vitro lipolysis
differ in some details between research groups, in vitro lipolysis is
commonly carried out in a temperature controlled vessel containing
lipolysis medium where the composition of the lipolysis medium is
chosen to reflect the conditions (e.g. pH, osmolality, bile salt and
phospholipid concentration) of the small intestine during either the
fasted or fed state. It should be noted that the physiological values
between individuals differ considerably requiring some compromise for
the experimental procedure. The pH of the constantly stirred lipolysis
medium is measured by a pH-electrode and can be adjusted using a
computer-controlled pH-stat device. Lipid digestion commences following the dispersion of the LbDDS and the addition of pancreatic
lipase and co-lipase to the lipolysis medium resulting in the release of
free fatty acids that are titrated with sodium hydroxide to maintain a
constant pH (Figure 2). The consumption of sodium hydroxide is an
indirect and unspecific method to measure the progress of lipolysis.
For example, the pH of the lipolysis medium could also change due
to the hydrolysis of impurities in excipients and the absorption of
carbon dioxide by the medium.
To account for this background lipolysis it is common practice
to subtract the sodium hydroxide volume required for the lipolysis of
377
23

Figure 3 - Schematic of the typical appearance of the lipolysis medium

after in vitro lipolysis and ultracentrifugation. An oil phase separates
from the aqueous phase in the case of an oil-rich formulation following
incomplete lipolysis. Drugs can distribute between the oil and water
phase, or precipitate along with calcium soaps. Adapted from [66].
Figure 2 - Illustration of a typical lipolysis set up. The temperaturecontrolled reaction vessel (I) contains the lipolysis medium agitated by
a magnetic stirrer (II). The temperature-sensitive pH-electrode (III) is
connected to the pH-stat unit (IV) controlling the dispensing of sodium
chloride (V) and calcium chloride (VI). The water bath (VII) maintains
the temperature of the lipolysis medium at 37C. Adapted from [66] .
that the highest bioavailability resulted after oral administration of

SNEDDS in which cinnarizine had the lowest solubility (equivalent to
a higher saturation level of 88% in the pre-concentrate) compared to a
SNEDDS with higher solubility (corresponding to 47 % drug saturation
in the pre-concentrate). Compared to conventional SNEDDS (drug
load well below saturation concentration) similar or increased bioavailability (Figure 4) was also observed for supersaturated SNEDDS
(super-SNEDDS) in which simvastatin and halofantrine were present
above the equilibrium solubility in the pre- concentrate [66, 76].
It is interesting to note, that cinnarizine, simvastatin, and halofantrine precipitated in an amorphous form during in vitro lipolysis, as
evidenced by XPRD [76-78]. In line with the higher energy associated
formulation-free lipolysis medium from the sodium hydroxide volume needed for the actual lipolysis experiment. For further chemical
characterization of specific lipid digestion products high performance
thin layer chromatography and evaporative light scattering have
been applied successfully [67, 68]. In addition to the aforementioned
chemical characterization of the lipolysis products several physical
approaches have been used to assess the evolution of the colloidal
phases during in vitro lipolysis. Using cryo transmission electron
microscopy Fatouros et al. observed the presence of oil droplets and
micelles as the prevailing structures before in vitro lipolysis of SNEDDS
was initiated [69]. Over the course of lipid digestion the oil droplets
gradually disappeared, giving rise to unilamellar and multilamellar
vesicles. These findings were confirmed in subsequent studies using
bench top and synchroton small angle x-ray scattering (SAXS) [55,
65, 69, 70].
In the dynamic in vitro lipolysis model employed in Copenhagen
the constant addition of calcium chloride controls the rate and extend
of in vitro lipolysis by the removal of the digestion products from the
lipid surface that would otherwise inhibit further lipolysis [71, 72].
Proceeding lipolytic activity in samples of the medium is inhibited by
the addition of lipase inhibitors such as 4-bromobenzene boronic acid.
This is followed by the quantification of the drug in the aqueous phase
and the pellet obtained after an ultracentrifugation step (Figure3).
LbDDS leading to drug precipitation during dispersion or in vitro
lipolysis have been generally regarded unsuitable for effective drug
delivery [73, 74]. This paradigm is based on the assumption that only
the solubilized drug present in the aqueous phase is available for absorption. Consequently, the general objective of most of the LbDDS
development has been to avoid or retard drug precipitation due to
concerns of re-introducing a dissolution step of solid drug.
A growing body of evidence, however, suggests revision of this
paradigm. Several studies have shown that drug precipitation does not
necessarily correlate with reduced bioavailability [61, 75-77]. In a recent
study investigating the effect of different physicochemical properties
of four different SNEDDS on the in vivo performance, Larsen et al.
observed comparable areas under the plasma curves of cinnarizine
although substantial drug precipitation during in vitro lipolysis was
evident for one of the SNEDDS [61]. Moreover, the authors found
Figure 4 - Semi-logarithmic plot of the mean plasma concentrations of

simvastatin (SIM) administered orally as (l) one capsule of conventional
SNEDDS (75% drug load, corresponding to 67.7 mg SIM), (s) two
capsules of conventional SNEDDS (75% drug load, 135.5 mg SIM),
and (u) one capsule of supersaturated SNEDDS (super-SNEDDS,
150% drug load, 135.5 mg SIM) to six fasted beagle dogs (mean
SD). AUC0-inf and bioavailability of simvastatin following administration of
super-SNEDDS were significantly greater compared to those obtained
after administration of dose-equivalent two capsules of conventional
SNEDDS. Adapted from [76].
378
24

with the amorphous form, the dissolution rate of these compounds

was substantially increased compared to the corresponding crystalline
forms. The data clearly demonstrate that caution is advised when attempting to predict in vivo results from in vitro performance. Further
studies are underway to investigate how the solid state of a compound,
drug loading in the pre-concentrates and the ability to supersaturate
SNEDDS are linked to their performance in vitro and in vivo.
It is perhaps the lack of an absorption step in the currently employed
in vitro lipolysis model that makes the in vivo prediction based on in vitro
results challenging. Cell culture studies using Caco-2 cells, commonly
employed in permeability studies of conventional formulations, have
proven difficult in light of the poor tolerance of these cells towards
the surfactants and bile salts frequently used in the formulation and
characterization of LbDDS [33, 79]. The shortcomings of the Caco-2
cell model might be overcome in the future by the development of

mucus producing Caco-2/HT29 co-cultures or Calu-3 cultures that
could protect the cell cultures to some degree during permeability
studies [80-82].
IV. In vivo testing of LbDDS
The number of in vivo studies comparing LbDDS both in vitro

and in vivo is still relatively small which is complicated further by the
choice of different animal models. Table III provides an overview of
recent pharmacokinetic studies concerned with the in vivo performance
of a range of LbDDS. Several animal models have been used in these
studies including rats, rabbits, minipigs, and dogs. Generally, the
selection of the animal model is defined by the research question and
economic considerations. Small animals such as rats and rabbits are
Table III - Recent in vivo studies with lipid-based delivery systems carried out in different animal species.
Type and composition of LbDDS*
Drug
Major outcome of the study
Animal species
Ref.
SMEDDS: Capryol 90 37 %, Cremophor EL 28 %,

Carbitol 28 %, 7 % simvastatin
Simvastatin
Relative bioavailability SMEDDS (1.5-fold)

> commercial tablet
Beagle dog
[88]
MCT (Viscoleo) and LCT (sesame oil)

MC-SMEDDS: MCT 25 %, Cremophor RH 40 45 %,
mixed MC-glycerides 27 %
LC-SMEDDS: LCT 25 %, Cremophor RH 40 45 %,
mixed LC-glycerides 27 %
Seocalcitol
Absolute bioavailability MCT = LCT > MCSNEDDS = LC-SNEDDS
Rat
[6, 92]
MCT (Viscoleo) and LCT (sesame oil)

MC-SMEDDS: MCT 25 %, Cremophor RH 40 45 %,
mixed MC-glycerides 27 %
LC-SMEDDS: LCT 25 %, Cremophor RH 40 45 %,
mixed LC-glycerides 27 %
Seocalcitol
Absolute bioavailability:
MC-SNEDDS = LC-SNEDDS > MCT = LCT
Minipig
[89]
Danazol
Solution / suspension in Labrafil M2125CS
(9-fold) > aqueous suspension
Rat
[35]
Oil solution: sesame oil, Maisine (1:1)

109.3 mg/kg, 12.1 mg/kg
Surfactant solution: Cremophor RH 40 109.3 mg/kg,
ethanol 12.1 mg/kg
SEDDS: sesame oil, Maisine (1:1) 72.8 mg/kg,
Cremophor RH 40 36.4 mg/kg, ethanol 12.8 mg/kg
SNEDDS: sesame oil, Maisine (1:1) 72.8 mg/kg,
Cremophor RH 40 36.4 mg/kg, ethanol 12.1 mg/kg
Probucol
Fasted: SNEDDS SEDDS surfactant
solution > oil solution > powder
Fed: SNEDDS = SEDDS, no food effect,
Reduced bioavailability for other formulations with considerable food effect
Minipig
[38]
CrEL-SEDDS: soybean oil, Maisine (1:1) 37.5 %,

Cremophor EL 55 %, ethanol 7.5 %
CrRH 40-SEDDS: soybean oil, Maisine (1:1)
37.5%, Cremophor RH 40 55 %, ethanol 7.5 %
Danazol
Relative bioavailability:
CrRH 40-SEDDS > CrEL-SEDDS
Beagle dog
[94]
Rabbit
[62]
Drug solution or suspension in Labrafil M2125CS
SMEDDS: Cremophor EL 30 %, Tween 80 15 %,

PEG 400 45 %, Capmul PG-8 10 %
Albendazol
SMEDDS (1.6-fold) > commercial suspension
LC-SNEDDS/LC-super-SNEDDS: soybean oil,

Maisine (1:1) 55 %, 35 % Cremophor RH 40,
ethanol 10 %
MC-SNEDDS/MC-super-SNEDDS: Captex 300,
Capmul MCM (1:2) 55 %, 35 % Cremophor RH
40, ethanol 10 %
Halofantrine
super-SNEDDS SNEDDS
Beagle dog
[77]
MC-SNEDDS/MC-super-SNEDDS: Captex 300,

Capmul MCM (1:2) 55 %, 35 % Cremophor RH
40, ethanol 10 %
Simvastatin
super-SNEDDS (1.8-fold) > SNEDDS
Beagle dog
[76]
SNEDDS I: sesame oil 26.3 %, oleic acid 17.6 %,

Cremophor RH 40 43.9 %, ethanol 9.7 %
SNEDDS IV: sesame oil 5.0 %, oleic acid 3.8 %,
Cremophor RH 40 52.7 %, Brij 97 17.6 %, PEG
400 8.8 %, ethanol 9.7 %
Cinnarizine
SNEDDS IV > SNEDDS I
Labrador dog
[61]
*Terminology as used by the respective authors, CrEL: Cremophor EL, CrRH40: Cremophor RH 40, MCT: medium chain triglycerides, LCT: long-chain
triglycerides, SNEDDS: self-nanoemulsifying drug delivery system, SMEDDS: self-microemulsifying drug delivery system, MC-SNEDDS/SMEDDS:
formulations containing medium-chain lipids, LC-SNEDDS/SMEDDS: formulations containing long chain lipids, super-SNEDDS: supersaturated SNEDDS.
379
25

relatively easy to manage and have been commonly employed as in

vivo models for absorption studies from drug solutions and powders
[83]. On the other hand, larger animals are more suitable to study
the bioavailability from formulations [83]. With regard to the in vivo
assessment of LbDDS, the most frequently used species are the rat
[35, 84-86] and the dog [53, 87, 88] whereas only very limited data is
available for minipigs [38, 89, 90]. While rats are less resource-intensive
than other animals they might not be the ideal species to investigate
LbDDS as they do not store bile in a gall bladder, but instead, have a
continuous bile flow, possibly affecting the digestion process outlined
above [83, 89]. In addition, the small size of rats limits the maximum
amount of formulation that can be administered [83, 91]. This can
have consequences for the dynamics of dispersing formulations as in
the case of SEDDS and SNEDDS [89]. Following the administration
of simple LbDDS composed of medium-chain (MC) and long chain
(LC) triglycerides the bioavailability of the drug seocalcitol did not
differ when evaluated in rats [92]. The obtained in vivo data were in
line with solubility studies carried out in simulated intestinal media
containing lipolysis products of the employed LbDDS. Compared to
MCT and LCT a slight decrease in the bioavailability was observed
when rats were given either MC- or LC-SNEDDS [6]. However, when
studied in minipigs, the MC-SNEDDS caused an increased bioavailability compared to the treatment with MCT. The authors hypothesized
that the limited volume of intestinal fluids present in the rat might
not generate a finely dispersed nanoemulsion but viscous gel-like
structures that could not unfold its full potential [89]. This example
emphasizes the need for the appropriate selection of the animal model
when evaluating LbDDS.
According to the previous discussion there might be some merit
in the use of larger animals to study LbDDS. Each animal model
requires careful consideration, or at least awareness, for its inherent
drawbacks. Critical factors to consider include the anatomy, pH, gastrointestinal motility, and surface area of the intestine [90, 93]. While
minipigs resemble the gastrointestinal physiology in humans closer
than dogs [83, 90] their intestinal anatomy and length differ in some
aspects [83]. The greater experience with dog models along with the
good agreement with many human data in previous bioavailability
and food effect studies renders the dog a suitable animal model for
the assessment of LbDDS. Until comparative studies across several
species are available (which would be very desirable) it appears that
both dogs and minipigs are better suitable for the assessment of LbDDS
than rats. Ultimately, a larger set of in vivo data will help elucidate a
more refined picture of the full potential of LbDDS.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Lipid-based drug delivery has great potential for the delivery of

poorly water-soluble, lipophilic drugs. However, to fully realize this
potential our knowledge about these complex delivery systems has to
advance considerably. The current review sought to highlight some of
the challenges encountered in the development and characterization
of LbDDS. Insights into drug absorption from LbDDS on a molecular level will aid in their rational formulation design. The need for a
standardized in vitro protocol, ideally incorporating an absorption step,
will be crucial for our understanding of these systems and to reliably
predict the in vivo performance. Advances in this research area will
ultimately elevate the currently empirical formulation process to a
safe and rational approach in the design and development of LbDDS.
19.
20.
21.
22.
23.
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Manuscript
Received 12 March 2013, accepted for publication 23 April 2013.
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A special article collection companion to the webinar

Strategies for formulating and delivering poorly water-soluble drugs

Amorphous drugs and dosage forms

Univ. Lille, F-59000 Lille, France

INSERM U 1008, F-59000 Lille, France

Journal of Drug Delivery Science and Technology xxx (2015) 1e10

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

Strategies for formulating and delivering poorly water-soluble drugs

of new chemical entities, 75% of compounds under development

Fig. 2. A schematic representation of the different strategies for formulating and

combined with other solubilizing approaches such as surfactants,

activation by viral thymidine kinase and cellular kinases to nally

rate. In general, a higher structural disorder in the solid leads to

their lower solubility, bioavailability and stability compared to the

2.2.4. Surfactants and lipids

cyclosporine A o/w emulsion for oral administration.

formation is linked to i) hydrophobic interactions, ii) release of the

2.3. Administration modication

On one hand, alternative administration routes can be used to

testosterone as the systemic options, while improving patient

[104] T. Loftssona, T. Jarvinen, Cyclodextrins in ophthalmic drug delivery, Adv.

J. Pharm. Sci. 90 (2001) 979e986.

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

Amorphous drugs and dosage forms

In the pharmaceutical industry, poor physicochemical properties

I. Prediction of amorphous stability

Ways of stabilising the amorphous state against recrystallisation and

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

Amorphous drugs and dosage forms

Results showed that no simple method exists to easily correlate

Figure 1 - Percentage amorphous content and relaxation time after

Graeser et al. published for the first time an approach where

II. The influence of process parameters

As stated above, the amorphous state can be produced by different

Figure 2 - (a) Configurational entropy and enthalpy vs. stability of the

Figure 3 - X-ray diffractograms of freshly prepared amorphous forms

Amorphous drugs and dosage forms

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

Taking the same preparation method but varying the parameters,

III. Amorphous drug formulations

The stabilisation of amorphous drugs is usually achieved by addition

Figure 4 - Crystalline content of amorphous indomethacin stored in

Another recent approach is to stabilise amorphous materials via

1. Glass solutions and solid dispersions

3. Co-amorphous drug formulations

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

Amorphous drugs and dosage forms

(GPZ)/simvastatin (SVS) [49]. In the study on IND and NAP, we

Figure 5 - XRPD patterns of physical stability study at various storage

Figure 6 - Schematic depiction of the research strategy using amino

Amorphous drugs and dosage forms

milling and contained either of the two drugs carbamazepine (CBZ)

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

gaining attention. Here suitable processes that enable the formation

Amorphous systems will gain in importance for the pharmaceutical

Hancock B.C., Zografi G. - Characteristics and significance of

J. DRUG DEL. SCI. TECH., 23 (4) 403-408 2013

Amorphous drugs and dosage forms

soluble compounds. - J. Pharm. Sci., 94, 1998-2012, 2005.

state. - J. Pharm. Sci., 86 (3), 346-351, 1997.