International Journal of Pharmaceutics 453 (2013) 233–252

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Melt extrusion with poorly soluble drugs

Sejal Shah, Sindhuri Maddineni, Jiannan Lu, Michael A. Repka ∗
Department of Pharmaceutics, Pii Center for Pharmaceutical Technology, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, United States

a r t i c l e i n f o a b s t r a c t

Article history: Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in
Received 7 June 2012 the drug development process. ME applications include taste masking, solid-state stability enhancement,
Received in revised form 31 October 2012 sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid
Accepted 1 November 2012
dispersions depending upon several factors, solubility enhancement applications are centered around
Available online 20 November 2012
generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with
the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubil-
Keywords:
ity of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology,
Melt extrusion
Poorly water soluble drugs
definition and understanding of the amorphous state, manufacturability, analytical characterization and
Dissolution rate enhancement biopharmaceutical performance testing to better understand the strength and weakness of this formu-
Solid dispersion lation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of
Amorphous system employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evapo-
Solid solution ration, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics.
Thermoplastic polymers Finally, the review presents some successful case studies of commercialized ME based products.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2. Solubilization using melt extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
3. Manufacturing aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.1. Equipment for melt extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.1.1. Downstream processing equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.2. Melt extrusion processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.3. Screw design and configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
3.4. Process analytical technology (PAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
3.5. Processing parameters and scale-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
3.6. Screening criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
4. Solubility enhancement using hydrophilic polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
5. Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
5.1. Spectroscopic techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
5.1.1. X-ray diffraction methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
5.1.2. IR and Raman spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
5.2. Thermal techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
5.2.1. Differential scanning calorimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
5.2.2. Isothermal microcalorimetry (IC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
5.3. Microscopic techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
5.4. Microthermal analysis (Micro-TA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
5.5. Water vapor sorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
6. Innovation in melt extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
6.1. Formation of co-crystals using melt extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
6.2. Fusion of solvent evaporation/spray drying techniques with melt extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

∗ Corresponding author. Tel.: +1 662 915 1155; fax: +1 662 915 1177.
E-mail address: marepka@olemiss.edu (M.A. Repka).

0378-5173/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2012.11.001
234 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252

7. Marketed formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

8. Comparison of different solid dispersion techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

1. Introduction Crystalline solid dispersions are generally designed to achieve

controlled drug release profiles for highly soluble drugs (Dierickx
The application of molecular modeling and high throughput et al., 2012; Ma et al., 2012; Roblegg et al., 2011; Verhoeven et al.,
drug innovation has led to discovery of numerous new chemi- 2009).
cal entities as potential therapeutic agents. However, obstacles Micro or nano crystalline solid dispersions also find applica-
associated with solubility, bioavailability and toxicity undermine tion in solubility enhancement. Thommes et al. (2011) describe a
their development and commercialization. The enhancement of system termed as solid crystal suspension (crystalline drug sus-
oral bioavailability of poorly water-soluble drugs remains one pended in crystalline carrier matrix) analogous to the crystalline
of the most challenging aspects of the drug development pro- solid dispersion, prepared using top down technique. This solid
cess. Pharmaceutical scientists, over the years have successfully crystal suspension was designed to improve the dissolution of three
developed several strategies for design of delivery systems for poorly water-soluble drugs. The system comprised of high melting
poorly soluble drugs. Solid dispersions prepared by melt extru- point drugs like griseofulvin (10% and 50%), spironolactone (10%)
sion (ME) technology is one such strategy that over the past and phenytoin (10%) and mannitol as a rapidly recrystallizing car-
three decades has resulted in several unique drug delivery rier phase. X-ray diffraction profile revealed the crystalline nature
systems. of extruded formulation similar to the combined pattern of crys-
Melt extrusion has been successfully applied to enhance solu- talline drug and excipients respectively. The dissolution rates of
bility of poorly soluble drugs (Feng et al., 2011; Lakshman et al., the extrudates were considerably higher than that for the pure
2008; Liu et al., 2012b; Sakurai et al., 2012; Tho et al., 2010). Sol- drug and physical mixture, attributable to the enhanced wetting
ubility enhancement in the melt extrusion process occurs through of the API by mannitol. Moreover, the crystalline character of the
dispersion of a poorly soluble drug(s) in a polymeric (or lipid) formulation was devoid of any physical stability issues, which is an
carrier matrix essentially forming a solid dispersion. According to inherent limitation with amorphous formulations. In addition, the
Chiou and Riegelman a solid dispersion is defined as ‘dispersion of melt extrusion processing reduced the particle size of API resulting
one or more API in an inert carrier in the solid state, prepared by in uniform distribution of API in the rapidly crystallizing manni-
either melting, solvent or the combined melting-solvent method’. tol matrix. Hence, the combined effect of melt processing and the
Further, they classify solid dispersions as eutectic mixtures, solid solid suspension of crystalline API in hydrophilic crystalline matrix
solutions and glass solutions based on the physical state of the drug appear to be a reasonable approach suitable for drugs that are dif-
and the carrier (Chiou and Riegelman, 1971). During melt extru- ficult to stabilize in the amorphous form.
sion of a drug within a polymer binary mixture, the drug could The bottom-up manufacturing process using hot melt extrusion
remain molecularly dispersed within the polymer or exists as an is described in a recent invention (Chatterji et al., 2012) that illus-
amorphous or crystalline phase. Hence, based on the molecular trates the formation of controlled crystalline solid dispersion of
state of the API distributed in the carrier phase and characteristic API from its super cooled liquid state. The invention describes a
thermal properties (drug melting temperature Tm /glass transition process, wherein the crystalline API is converted to non-crystalline
temperature Tg or melting temperature Tmc of the carrier phase form by application of heat and shear up to 1/4th to 3/4th of the
as identified by DSC) of the system, solid dispersions prepared by barrel length followed by a recrystallization zone in the remaining
HME can be categorized as crystalline solid dispersions, amorphous barrel length, wherein cooling is applied. The cooling of the bar-
solid dispersions, and solid solutions (also regarded as a subgroup rel initiated API nucleation that promoted crystal growth while
of amorphous solid dispersions) (Fig. 1) (Janssens and Van den the shearing action of the screws evenly distributes the nuclei and
Mooter, 2009; Leuner and Dressman, 2000; Serajuddin, 1999). A hence controls the mean particle diameter of the newly formed
thorough understanding of structure of a solid dispersion, partic- crystalline API. The particle size of newly formed crystalline API
ularly the existing physical form of a drug in the carrier matrix is is significantly lesser than the bulk API. Recrystallization of the
required to predict the stability, solubility and hence bioavailability API is controlled by carrier formulation design and ME process
of melt extrudates. parameters like barrel temperature, feed rate, etc. The crystalline
Crystalline solid dispersions are systems wherein the crystalline drug, dalcetrapib, is unstable in its amorphous state; hence, the
drug substance is dispersed into an amorphous carrier matrix. The aforementioned processing technique was found to be a rather
DSC profile for such a system is characterized by the presence of a suitable method of production. In addition, the rapid dissolution
melting endotherm (Tm ) corresponding to the crystalline API and a was observed as compared to its micronized form. However, this
characteristic glass transition temperature (Tg ) corresponding to approach faces technical challenges such as maintaining consis-
the amorphous carrier. Crystalline solid dispersions can be pre- tent batch-to-batch crystallization (particle size of crystals), and
pared using either the top-down or bottom-up techniques. The detection of residual amorphous drug content.
bottom-up process, encompassing the growth of small particles Amorphous solid dispersions result when melt extruded
from individual molecules is attributed to the immiscibility or drug–polymer is cooled at a rate that does not allow the drug to
supersaturation of API in the carrier phase either in molten or solid recrystallize or processed at temperatures where drug melts but
(after cooling) form of the extrudates. It is important to note that, remains immiscible with the carrier. Such processing results in
in either of the techniques for the drug to be 100% crystalline in the kinetic entrapment of the drug in its amorphous state. Although,
carrier matrix, it should be completely immiscible with the carrier these types of systems exhibit increased rate of dissolution due
phase at the employed processing conditions. Moreover, for the top to high thermodynamic activity, they have a potential to revert to
down technique, the Tm of the drug is essentially greater than the the more stable crystalline form (Janssens and Van den Mooter,
Tg of amorphous carrier. 2009; Leuner and Dressman, 2000). In a solid solution, the drug
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Fig. 1. States of solid dispersion.
molecule is molecularly dissolved in the polymeric carrier matrix
and exhibits a single glass transition temperature (Tg ). An amor-
phous solid solution is a pharmaceutically desirable single-phase
system preferably including an amorphous polymer as the carrier,
a drug in its high-energy state, as well as other excipients such as
processing aids, recrystallization inhibitors, and wetting agents.
Melt extrusion application for solubility enhancement aims at
generating amorphous solid dispersions. Amorphous solid dis-
persions not only offer the inherent free energy benefits of an
amorphous system, but also provide maximum specific surface area
and higher saturation solubility, which ultimately increase drug
solubility. Thorough understanding of the physicochemical proper-
ties of amorphous solid dispersions and their corresponding in vivo
behavior is required for the realization of their true potential in the
pharmaceutical industry. Van den Mooter has extensively reviewed
the application of amorphous solid dispersions as an interesting
strategy to increase the bioavailability of poorly soluble drugs (Van
den Mooter, 2012). Van den Mooter discusses important aspects
such as the amorphous state, manufacturing, characterization, and
biopharmaceutical testing for better understanding of the strength
and weakness of solid dispersions.
It is a general understanding that amorphous solid dispersions
enhance the solubility and hence improves bioavailability of drugs;
however, it is certainly not a universal rule applicable to all drugs.
Newman et al. make a comparative assessment of the performance
of amorphous solid dispersions, described in 40 research papers
(Newman et al., 2012). The results from this comparative assess-
ment are classified into 3 categories (i) amorphous dispersions with
improved bioavailability (82% of the cases); (ii) amorphous disper-
sion with no change or similar bioavailability to reference material
(10% of the cases); (iii) amorphous dispersions with lower bioavail-
ability (8% of the cases). An analysis of these studies revealed several
in vitro and in vivo variables that could influence the results. Based
on these variables, they make several recommendations for consid-
erations in the standardized performance evaluation of amorphous
solid dispersions.
235
While HME has several advantages, it is limited because of
its inability to process heat sensitive or high melting point
drugs. Moreover, HME is an easily scalable method for large-
scale commercial manufacture but HME (primarily the equipment)
is generally not amenable for scale-down manufacturing and
screening (processing mg to g quantities of drug product) typi-
cally required in early stage development. In addition, the analytical
characterization methods are limited in terms of detecting phase
separation in amorphous dispersions or quantifying trace levels of
crystallinity. The strategies adopted to overcome these limitations
(miniaturized screening methods for early stage development, local
and global analytical methods for detection of phase separation,
quantification methods for residual crystallinity) are discussed in
sufficient detail in subsequent sections.
This review highlights major aspects of melt extrusion
technology, the amorphous state, manufacturing, analytical char-
acterization and biopharmaceutical testing to better understand
the strengths and weaknesses of this formulation strategy for
poorly soluble drugs. Furthermore, this paper presents some suc-
cessful case studies of commercialized ME based products.
2. Solubilization using melt extrusion
Successful solubilization in melt extrusion is determined by
several factors, which are material (drug and carrier proper-
ties), process (processing temperature, shear, etc.) and equipment
(design and operating conditions) related. We discuss the mate-
rial and process related factors in this section, equipment related
factors are discussed in the subsequent section. Processing temper-
ature is an important parameter in melt extrusion. Ideal processing
temperature is selected based on the melting temperature (Tm ) of
the drug, Tmc /Tg of the carrier and is generally greater than the
Tmc /Tg of the carrier. Such high processing temperatures ensure
that the carrier is softened (often melted) and possess low viscosity,
thereby permitting extrusion. Processing aids such as plasticizers
236 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
can be added to improve the flow of the melt. Ideally, the Tmc or Tg
of carrier should not be too high since high temperature processing
may potentially lead to drug degradation.
DiNunzio et al. (2012) classify melt extrusion processing into
two distinct regimes, based on extrusion temperature (Tprocess )
employed and the melting temperature (Tm ) of the drug. In the sol-
ubilization regime, Tprocess < Tm whereas in the miscibility regime,
Tprocess ≥ Tm however the glass transition temperature (Tg ) of the
carrier is well above the Tprocess in both the regimes (DiNunzio et al.,
2012).
The miscibility of drug phase in the molten carrier matrix
predominantly dictates the successful preparation and hence sta-
bilization of amorphous solid dispersion in the miscibility regime.
In addition, the appropriate selection of screw configuration and
the shearing action of screws during hot melt processing assist in
homogeneous dispersion of the drug in the molten carrier phase.
Processing under miscibility regime is limited due to its inability to
process high melting point drugs. Various approaches such as dif-
ferential solubility parameter (<7 MPa1/2 ) (Greenhalgh et al., 1999),
Floury–Huggins mixing theory (Abu-Diak et al., 2012; Yang et al.,
2012; Zhao et al., 2011), Gordon–Taylor equation with appropriate
assumptions and modifications (Forster et al., 2001a), determina-
tion of Tg using DSC in conjunction with mid IR and XRPD with
computational analysis (Rumondor et al., 2009a), etc. are employed
to assess the drug–polymer miscibility.
The processing under solubilization regime is better understood
by Noyes–Whitney equation, wherein increased dissolution rates
(dM/dt) of crystalline drug in the molten carrier matrix could be
achieved by raising the temperature of the system (i.e. processing
above the glass transition temperature of carrier phase) that would
result in increased equilibrium solubility (C0 ) and diffusivity (D) of
the drug in the molten carrier phase.
dM DA
= × (C0 − Ct )
dt h proposed that at the temperature 50 ◦ C lower than Tg , the molecu-
Each of the terms in the above equation (Eq. (1)) can be altered to
ultimately achieve high dissolution rates (dM/dt), surface area (A)
of the drug can be increased by micronization. Increased dissolu-
tion time (t) can be achieved by increasing the mean residence
time of the dispersion in the extruder, increased solubility (C0 ) and
diffusivity (D) could be achieved by raising the processing tem-
perature or by addition of co-solvents, plasticizers, etc. Applying
more shears (suitable screw configuration and screw speed) to the
system would result in further reducing the viscosity (decrease in
boundary layer thickness, h) and thereby enhancing the diffusivity
and dissolution rate of the drug in the carrier phase.
Processing under this regime is most appropriate for high-
melting point and heat sensitive drugs.
Certain modifications such as micronization of the drug sub-
stance prior to extrusion serve as an effective means to enhance
the surface area and hence the drug dissolution rates in the molten
polymer, thereby improving the melt extrusion processing and the
performance of melt extruded product. Hughey and co-workers
describe the preparation of Eudragit® L100-55 based amorphous
dispersions of micronized Roche Research compound A (ROA). It
was identified that micronization and reduced residence time were
necessary for generating amorphous dispersions. Hughey et al.
(2010) compare Kinetisol® dispersion technique and the hot melt
extrusion method as a means to prepare dissolution enhanced solid
dispersions of ROA. Miller and co-workers describe the preparation
of melt extrudates of micronized particles of amorphous itracona-
zole stabilized with PVP or HPMC. PEO 200 M and poloxamer 407
were employed as deaggregation and dispersing agents during
extrusion. Analytical characterization demonstrated that HME did
not alter properties of micronized particles. Further, dissolution
rate of the micronized particles was improved due to particle deag-
gregation and enhanced wetting (Miller et al., 2007).
Like process temperature, the polymeric carrier is also impor-
tant and has a significant impact on the success rate of the solid
dispersions. Inherent melt solubility is an important aspect for car-
rier selection, as this significantly limits the range of materials
that can be used as carriers for solubilization. The carrier should
be heat stable at the employed processing temperature, pharma-
cologically inert and safe. In addition, thermal stability and melt
viscosity are important considerations for melt extrusion carri-
ers. Aqueous solubility of the carrier is an obvious requirement.
Janssens and Van den Mooter (2009) have extensively reviewed
the most important carrier properties and provide an overview of
the polymers that have been used in commercial marketed for-
mulations. Physical stability of amorphous solid dispersion could
be improved by anti-plasticization effect of polymers (increasing
the viscosity of the binary system and decreasing the diffusion of
drug molecules) that would raise the glass transition temperature
of the system (Kakumanu and Bansal, 2002; Sathigari et al., 2012;
Van den Mooter et al., 2001). Hydrogen bonding and hydrophobic
interactions between the drug and polymer are the primary driving
forces for the formation of solid dispersions during melt extrusion,
inhibition of drug crystallization during subsequent storage of melt
exudates and achievement and sustainment of supersaturation in
the GI tract.
The solubility and miscibility of drug in the polymer are directly
related to the stabilization of an amorphous drug against crystal-
lization (Qian et al., 2010). Unfortunately, the amorphous state is
less stable than the crystalline state, at times resulting in the recrys-
tallization of drug from solid dispersions during the manufacturing
process and subsequently during storage (Vasconcelos et al., 2007).
Below the Tg , which represents a kinetic boundary of molec-
ular mobility, the stability of solid dispersions strongly dependent
upon kinetics of phase separation and crystallization. Yoshioka et al.
(1)
lar mobility can be neglected and the amorphous solids are stable
enough over a period of years (Hancock et al., 1995; Yoshioka et al.,
1995). This concept is popularly referred to as the ‘Tg − 50 ◦ C’ rule.
While this rule is valid in most cases, there are some excep-
tions (incompatibility when Tg − Tstorage > 50 ◦ C and stability when
Tg − Tstorage < 50 ◦ C) (Forster et al., 2001a; Vyazovkin and Dranca,
2007). This is probably because the concept takes into account only
the primary relaxations (“␣” relaxations or global mobility), which
are less significant below Tg . Secondary relaxations (“␤” relaxations
or local mobility) therefore also need to be considered as these
lead to nucleation at temperatures below Tg where the coopera-
tive “␣” relaxations are negligible (Grzybowska et al., 2010). “␤”
relaxations are associated with the movement of only a part of
a molecule, e.g. polymer side chains and occur on a smaller time
scale than the primary “␣” relaxations (relaxation time being typ-
ically < 10−1 s) (Bhattacharya and Suryanarayanan, 2009). Stability
even with Tg − Tstorage < 50 ◦ C, is attributed to specific intermolecu-
lar interactions (e.g. hydrogen bonding or ion–dipole interactions
between the drug and polymer) which results in an elevated acti-
vation energy for recrystallization (Khougaz and Clas, 2000; Konno
and Taylor, 2006; Matsumoto and Zografi, 1999; Miyazaki et al.,
2004; Taylor and Zografi, 1997).
Presence of moisture (inherent, during processing or stor-
age) is an important factor resulting in deviation from ideality.
Moisture due to its plasticizing effect increases the molec-
ular mobility and results in depression of the system Tg
(Marsac et al., 2010; Rumondor et al., 2009b). Moisture induced
amorphous–amorphous phase separation has also been studied
(Rumondor et al., 2011)
Qian et al. (2010) described challenges in development of solid
dispersions. In addition, these researchers highlighted investigative
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
strategies to better understand the destabilization mechanism of
amorphous solid dispersions.
Successful development of ME based amorphous formulations
depends on a robust preformulation assessment. The selection of
optimal processing conditions depends primarily on the chemical
stability of both the drug and the polymer and the physical proper-
ties of the polymer. Preformulation considerations to establish the
most appropriate process parameters for ME are solubility, drug
melting point (Tm ), glass transition temperature Tg of the polymer,
processing temperature (Tprocess /THME ), drug–polymer miscibility
and melt viscosity of the polymer. These have been extensively
studied by several workers (Breitenbach, 2002; Chokshi et al., 2005;
Forster et al., 2001a,b; Marsac et al., 2006) and have been reviewed
in sufficient detail (Crowley et al., 2007; Repka et al., 2007, 2008)
3. Manufacturing aspects
Based on the ongoing developments in fundamental material
sciences and engineering innovations, melt extrusion technology in
the pharmaceutical industry is now considered an evolved science.
The processing equipment for ME has been extensively developed
and it is now a common understanding in the field that formula-
tion ultimately defines the equipment design and the processing
parameters and vice versa. Furthermore, both formulation and
processing conditions determine key product quality attributes.
There are several studies describing these influences during melt
extrusion (Dinunzio et al., 2010a; Repka et al., 1999; Schilling et al.,
2007).
Early stage formulation development studies should primarily
focus on the interplay of formulation and processing conditions
using rational approaches. While the primary aim of early stage
studies is to develop a basic formulation and a process that supports
late stage development, early stage development also focuses on
the identification of critical process parameters governing product
attributes. Sufficient time and effort is spent in understanding the
effect of processing conditions on important process parameters
and hence formulation attributes.
Both early and late stage developments employ a Quality by
Design (QbD) based approach wherein target product profile is
well defined and critical quality attributes have been established.
QbD employs risk assessment by linking material properties and
process parameters to critical quality attributes. Successful under-
standing of the formulation-process interplay during early stage
development facilitates the determination of design space and
presents an efficient control strategy for critical product quality
attributes at late stage development including large-scale man-
ufacturing. Large-scale commercial production requires a robust,
scalable, and transferable process (Food and Drug Administration
Quality systems approach to pharmaceutical cGMP regulations,
2006). For the purpose of this review, the authors emphasize only
on the engineering improvisations for stringent process control and
hence better melt extruded formulation development. The fun-
damental engineering aspects of hot melt extrusion equipment,
although extremely important, are reviewed in sufficient detail
elsewhere (Breitenbach, 2002; Crowley et al., 2007; Repka et al.,
2012) and hence discussed in limited details herein.
3.1. Equipment for melt extrusion
Although developed in the plastic industry, the equipment and
operational units of melt extruders have been well adapted to
meet the specific demands of pharmaceutical industry and are con-
tinuing to do so. Over the years, engineering and manufacturing
companies have taken special efforts to design modular pharma-
ceutical grade extruders, in accordance with the current Good
Manufacturing Practice (cGMPs) norms.
237
Fig. 2. Illustration of a hot melt extrusion film assembly. (Courtesy of Thermo Elec-
tron Corporation, MA.)
The basic components of an extruder are the feeder, barrel
(screws or ram), control panel, torque sensors, heating/cooling
device, assorted dies, and downstream processing machinery
(Fig. 2). Screw extruders and ram extruders are two commonly
used extruders for pharmaceutical processing. Screw extruders can
be further classified based on certain fundamental properties such
as, number of screws, screw size, the direction of rotation of the
screws and the degree of element intermeshing. Screw extrud-
ers used for pharmaceutical applications typically consist of two
screws (twin-screw) and are further categorized as co-rotating and
counter-rotating, depending on the direction of rotation of the
screw.
Co-rotating being used for most applications, with the excep-
tion that sometimes counter-rotating (non-intermeshing type) is
employed when a small processing window is needed for heat sen-
sitive materials. However, the ultimate choice of screw extruder
depends upon several factors, material properties being the most
important of them. Unlike a screw extruder, a ram extruder opera-
tes by a positive displacement ram, which can push the material
through the die driven by high pressure.
3.1.1. Downstream processing equipment
A number of downstream processing equipment have been
developed and utilized in the hot melt extrusion process meet-
ing the requirements of final dosage forms. Dies in varying sizes
and shapes are available for formulation development. Flat dies are
utilized for production of films and sheets, circular dies are used
for pelletization and spheronization whereas the annular dies are
used for medical devices and tubing. Air, nitrogen, water, or stain-
less steel conveyors are used for the cooling of extrudates. Chill
rolls have been utilized for film production, wherein adjusting the
rotating speed of chill rolls as well as the die opening controls
the thickness of films. Take-up rolls and flakers are also used for
downstream processing of melt-extruded materials.
3.2. Melt extrusion processing
In general, the API and polymers are premixed with other excip-
ients or individually fed into the extruder. The physical mixture is
further extruded under a defined thermal and mechanical condi-
tion as a continuous process to generate a final product of uniform
size, shape, and content. From the standpoint of processing, ME can
be theoretically sub-divided into five steps: (1) feeding, (2) melt-
ing and plasticizing, (3) conveying and mixing, (4) venting and (5)
stripping and down-stream processing (Dreiblatt, 2003). Each of
these steps can affect the properties of the final extrudates.
238 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Feeding of extruders can be either in the “starve-fed” or the
“flood-fed” mode. For pharmaceutical processing, feeding is com-
monly conducted in a “starve-fed” mode, which results in efficient
mixing of the feed material as opposed to flood feeding. Starve feed-
ing primarily uses gravimetric or volumetric feeders to dispense
the material directly into screws, that prevents the accumulation
of the feed material at the feed zone and thus the mass flow rate is
independent of screw speed. At steady state, in a starve-fed mode,
the mass flow rate at the feed zone is equal to the mass exiting the
barrel and thus accumulation in the barrel is negligible. However,
screw speed can have a significant influence on the residence time
distribution of the feed material (Rauwendaal, 2001).
The different zones of the barrel are pre-set to specific tempera-
tures prior to the extrusion process. The material is introduced into
the feed section of the extruder via a hopper. Ideal flow properties of
the feedstock are controlled by the angle of the feed hopper, which
normally exceeds the angle of repose of the feed material. Other
factors such as moisture content, aeration, material density, and
morphology also affect the feeding properties. The feedstock is fur-
ther transported along the length of the barrel, where it is melted,
plasticized, mixed, and compressed. The shear forces created by
rotating screws as well as the heating elements in the barrel gener-
ate the required thermal energy. Mixing influences the properties
of the final product and is either distributive mixing or dispersive
mixing. Distributive mixing refers to the content uniformity of a
particular ingredient (e.g. the API or plasticizer) while dispersive
mixing relates to the size reduction and distribution (Repka et al.,
2002).
3.3. Screw design and configuration
The efficiency of the melting process is directly related to
the polymer’s properties and the extruder design. The screw ele-
ments can be functionally categorized into zoning, mixing and
conveying elements respectively (Steiner, 2003; Thiele, 2003). Each
of these elements affects the characteristics of the final prod-
uct. The materials, while being mixed by the force generated
within a mixing element, are transported from the feeding zone
to the downstream regions by the conveying elements. There
are limited reports, however, on the effect of screw design and
configuration on hot melt extrusion processing. One such exam-
ple is the study of kneading paddle elements of the twin-screw
extruder. Nakamichi et al. (2002) demonstrated that the kneading
paddle elements play an important role in changing the crys-
tallinity and dissolution properties of a solid dispersion of kneaded
nifedipine–hydroxypropylmethylcellulose phthalate. Verhoeven
et al. (2008) described that the distribution homogeneity and the
release rate of metoprolol tartrate in ethyl cellulose mini-matrices
were not significantly affected by the number of kneading mix-
ing zones or their positions along the extruder barrel and that at
least one kneading/mixing zone was required for homogenous dis-
tribution. Liu et al. studied the effects of screw configuration on
the dissolution behavior of indomethacin in Eudragit EPO melt
extrudate. Further they identified that that the kneading blocks
accelerated the complete dissolution process of indomethacin in
polymer melt (Liu et al., 2011).
3.4. Process analytical technology (PAT)
Process analytical technology (PAT) has gained much atten-
tion and application in the pharmaceutical industry (Gnoth et al.,
2007; Rathore et al., 2010; Read et al., 2010; Rodrigues et al., 2006;
Scott and Wilcock, 2006; Yu et al., 2004) and has been encour-
aged by FDA over the last decade (Food and Drug Administration,
2004). PAT can be used as a tool to monitor, analyze, and char-
acterize melt extrusion and chemical composition of the products
in line to ensure final desired product attributes. Using PAT as an
analytical tool, flow properties, polymer structures, polymer–drug
interactions as well as concentrations of drugs and additives can
be determined immediately downstream of the extrusion process.
Several analytical techniques (rheometric, optical, ultrasonic, elec-
trical, spectroscopy (Raman and Near-infrared (NIR) spectroscopy)
have been successfully incorporated into PAT for pharmaceutical
manufacture. However there are limited reports of applications of
PAT in the pharmaceutical melt extrusion process (Saerens et al.,
2011, 2012), indicating that the true potential of this analytical
methodology has not yet been fully realized.
3.5. Processing parameters and scale-up
Scaling-up in ME like other manufacturing technologies, is an
important subject of discussion and review (Lowinger, 2011). Guns
et al. (2012) discuss scale-up aspects of melt extrusion and make
a comparative assessment of miconazole and Kollicoat® IR solid
dispersion prepared by laboratory scale and pilot scale extrusion
respectively. The properties of the final dosage forms are indeed
affected by the processing parameters (screw speed, processing
temperature, and feed rate) of the melt extrusion process. The
screw speed and feed rate are also related to shear stress, shear
rate, and mean residence time, which in turn affect the disso-
lution rate and stability of the final products. Certain minimum
processing temperatures are required in the ME process to reduce
the torque needed to rotate the screw. Typically, the temperature
of the melting zone is set 15–60 ◦ C above the melting point of
semi-crystalline polymers or the glass transition temperature of
amorphous polymers (Mccrum and Buckley, 1997; Rauwendaal,
1994). The torque is directly proportional to the viscosity of the
molten feedstock. The viscosity of the polymer at a fixed shear
rate can be expressed by the Arrhenius equation (Repka et al.,
2002):
 = K  × eEa /RT (2)
where  is the viscosity of the polymer melt, K is a constant depend-
ing on the structure and the molecular weight of the polymer; Ea
is the activation energy of the polymer for the flow process and is
a constant for the same type of polymer; R is the gas constant; and
T is the temperature in Kelvin in Eq. (2).
As described earlier, during early stage formulation develop-
ment, the processing parameters provide the necessary design
space for subsequent scale up. Additionally, stringent control
of processing parameters in turn provides a robust formulation
while maintaining the quality and increasing the production effi-
ciency. Residual crystallinity, torque, and degradation are the
common dependent variables. Meanwhile, using design of exper-
iment (DOE), the effect of a single processing parameter on
formulation as well as the interplay between formulation and
processing parameters has been studied (Verreck et al., 2003). Shi-
bata et al. identified critical process parameters (residence time,
screw rotation speed and heating temperature) that play an impor-
tant role in the preparation of indomethacin–crospovidone solid
dispersion by twin-screw extrusion or kneader (Shibata et al.,
2009).
Liu et al. studied the effects of extrusion process parameters
(mixer temperature, screw rotating speed and residence time)
on the dissolution behavior of melt-extruded indomethacin in
Eudragit E PO. It was observed that an increase in the mixer tem-
perature or the screw rotating speed, related to the corresponding
increase in dissolution rate. Also, the residence time for an extru-
sion process and the drugs solubilization time in molten polymer
were found to be in a similar range (Liu et al., 2010).
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252 239

3.6. Screening criteria

The physical and chemical properties of APIs and carriers need

to be carefully assessed prior to developing melt-extruded formula-
tions. For example, the aqueous solubility and melting point of the
drug substance and the glass transition temperature of the poly-
mers will affect the miscibility or solubility of the drug substances in
the solid dispersion systems, which will in turn affect stability. The
other properties of APIs and polymers that affect the final formu-
lation include but are not limited to hydrogen-bond acceptor and
donor groups, molecular weight, hydrophobicity, log P, and Tm /Tg
ratio. A comprehensive discussion on selection criteria for suitable
polymers could be referred to for further details (Shah et al., 2012).
Solubility parameters may be calculated to predict the mis-
cibility of the drug/polymer systems. The dispersive, polar and
hydrogen bonding moieties of drug and polymer structures con-
tribute to the results of solubility parameters (Eq. (3)). It has been
advocated that if the differential value between drug and polymer
is less than 7.0 MPa1/2 , the system is most likely miscible, while dif-
ferential value greater than 10 MPa1/2 is indicative of immiscibility
(Greenhalgh et al., 1999).

Solubility Parameter Equation : ı2T = ı2d + ı2p + ı2h (3)

The lattice based Floury–Huggins equation was originally used to

study the polymer–solvent or polymer–polymer miscibility based
on Gibbs free energy change before and after mixing. However, it
was discovered that it may also be suitable for small molecules
and polymer systems (Zhao et al., 2011). An attempt was made to
determine interaction parameter () of the model system at two
different conditions with the utilization of Nishi–Wang equation
based on melting point depression data (Nishi and Wang, 1975) and
Hildebrand and Scott correlation (Hildebrand and Scott, 1950) with
solubility parameter respectively. Temperature-composition phase
diagram generated a spinodal curve, which serves as a boundary
between the unstable and metastable regions. Below this curve,
the system would spontaneously form two phases.
4. Solubility enhancement using hydrophilic polymers
Hydrophilic carriers, including polyvinylpyrrolidone and
polyvinylpyrrolidone-co-vinyl acetate, polyethylene gly-
cols, polyethylene oxides, some celluloses, polymethacrylate
derivatives (most of which find application in enteric drug
delivery systems), and a polyvinyl caprolactam–polyvinyl
acetate–polyethylene glycol graft copolymer have been suc-
cessfully used to improve the solubility and hence bioavailability
of water insoluble compounds using melt extrusion techniques
by the solid dispersion mechanism (Table 1). The selection of
a suitable carrier mainly depends on the following factors, the
solubility/miscibility of drug–polymer systems, the polymer
physico-chemical properties, stability, as well as the prerequisites
of the final dosage forms.
McGinity and Koleng (1997) prepared acetaminophen (APAP)
hot melt extruded granules with low molecular weight polyethy-
lene glycol (PEG), which were later compressed into tablets. 80%
APAP was released within 30 min from the tablets containing
melt extruded granules with 15% PEG. Rubessa and co-researchers
investigated the possibility of PEG 4000 as a potential rapid release
carrier for a poorly water-soluble compound, carbamazepine. The
extrudates demonstrated a more rapid release compared to the
physical mixture (Perissutti et al., 2002). Lu et al. developed a
supersaturated paclitaxel formulation using polyethylene oxide
(PolyOx® N80) as the primary carrier. The solubility of paclitaxel
was increased up to 9-fold compared to the pure drug. How-
ever, with the addition of hydroxypropylmethylcellulose acetate
Fig. 3. (a) Dissolution of melt extruded solid dispersions of paclitaxel and pure durg
and (b) FT-IR studies of extrudates, physical mixture, excipients and paclitaxel.
Reprinted with Permission of The AAPS Journal (Lu et al., 2011), Copyright (2011).
succinate (HPMCAS), the solubility of paclitaxel was maintained
up to 12 h. FT-IR studies were conducted to determine the inter-
actions between polymer and drug, which it is believed to be the
possible mechanism of precipitation inhibition. The stretch peak
of the O H group in pure paclitaxel at 3468.02 cm−1 as well as the
stretch peak of the carbonyl group at 1703 cm−1 were absent in
the spectrum of the extrudates, which confirmed the formation of
hydrogen bonding with HPMCAS (Fig. 3a) (Lu et al., 2011).
Numerous studies have been conducted on the solu-
bility enhancement of water insoluble compounds using
polyvinylpyrrolidone (PVP) or its derivatives as a carrier. Fu
et al. prepared a nimodipine–PVP VA solid dispersion tablet using
hot melt extrusion technology. The dissolution profile of ME
tablets was compared with the commercial product Nimotop® (Fu
et al., 2010). The melt extruded tablets exhibited a faster release
over Nimotop® , however, the ME tablets demonstrated a reduced
dissolution profile after 20–30 min, indicating a recrystallization
behavior due to supersaturated nimodipine in the dissolution
medium. The bioavailability of ME tablets were further investi-
gated in beagle dogs and the solid dispersion tablets illustrated a
similar Cmax and AUC as Nimotop® . A physically and chemically
stable solid dispersion of a new chemical entity manufactured
by Novartis Pharmaceuticals Corp. was developed by Lakshaman
et al., using polyvinylpyrrolidone K30 (PVP-K30) as a carrier
(Lakshman et al., 2008). The water insoluble API was converted
to an amorphous state and the formulation demonstrated a
more rapid release compared with the control formulation under
non-sink conditions. Furthermore, both of the melt extruded
solid dispersions containing 20 and 30% drug loading dispersions
240 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252

Table 1
Hydrophilic polymers for solubility enhancement.

Chemical Name Trade name Tg (◦ C) Tm (◦ C)

®
Polyvinyl Soluplus 70 –
caprolactam–polyvinyl
acetate–polyethylene
glycol graft
copolymer
Polyethylene oxide PolyyOx® WSR −57 to −50 62–67
Poly(vinyl Kollidon® , Plasdone® 90–156 –
pyrrolidone)
Polyvinylpyrrolidone- Kollidon® VA64 101 –
co-vinyl
acetate
Poly(dimethylaminoethylmethacrylate- Eudragit® E 50 –
co-methacrylic
esters)
Hydroxypropyl Aqoat-AS® ∼120 –
methylcellulose
acetate
succinate
Hydroxypropyl KlucelTM Softens at 130 ◦ C Chars at 260–275 ◦ C
cellulose
Hydroxypropyl Methocel® , Benecel® 160–210 –
methylcellulose
◦
Polyehtylene glycol Carbowax ®
−17 C for MW 6000 37–63
Polyvinyl Kollicoat IR® 45 208
alcohol–polyethylene
glycol copolymer
Poly – –
(lactic-co-glycolic
acid) (PLGA)
Cyclodextrin CAVAMAX®
Poloxamer Lutrol® F 127 – 55

demonstrated a significantly higher bioavailability compared with temperatures and relative humidities (4 ◦ C, 25 ◦ C/60%RH, 30 ◦ C,
the control formulation containing 20% crystalline drug triturated 70%RH, 40 ◦ C/75%RH, and 50 ◦ C) (Verreck et al., 2003). A compara-
with poloxamer in this dog model. The 20% drug loading solid tive study described the use of three HPMC based polymers (HPMC
dispersion was selected for further studies and was proven as 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPM-
physically and chemically stable at controlled room temperature. CAS)) as carriers in ME based solid dispersions. Solid dispersions of a
Other types of widely used polymers in melt extrusion are water insoluble drug, NVS981 were prepared using the HPMC based
cellulose and its derivatives, including hydroxypropyl cellulose polymers at drug loadings of 20 and 50%, respectively. The HPMC
(HPC), hydroxypropyl methylcellulose (HPMC, hypromellose) and 3cps and HPMCAS demonstrated better extrudability compared to
hydroxypropylmethylcellulose acetate succinate (HPMCAS). A HPMCP (partially due to the lower Tg and viscosity), However, the
recent study from Repka’s research group illustrated the util- NVS981–HPMCP exhibited a considerably higher release rate, even
ity of low molecular weight hydroxypropyl cellulose, KlucelTM under non-sink conditions, which was attributed to the possible
ELF hydrophilic matrices for the solubilization of poorly soluble strong interactions between the polymer and the drug (Ghosh et al.,
drugs. The immediate release ME tablets of the poorly water sol- 2011).
uble drug, ketoprofen (KPR), using KlucelTM ELF as a carrier were
found to exhibit similar release profiles as commercially available
50 mg capsules of ketoprofen. Therefore, the results demonstrated
KlucelTM ELF as a potential alternative carrier when produced by
ME (Mohammed et al., 2011). Moreover, different grades of low
molecular weight HPC polymers including KlucelTM ELF and EF
were utilized to improve the dissolution rate of a low Tg model drug,
fenofibrate. The dissolution rate of fenofibrate was significantly
increased compared to the pure drug (p < 0.05). Incorporation of
sugars within the formulation was observed to further benefit the
release of fenofibrate (Fig. 4). In addition, polyvinylpyrrolidone
17PF and amino methacrylate copolymer (Eudragit® E PO) exhib-
ited a significant inhibitory effect on fenofibrate recrystallization
in the melt extrudates serving as a stabilization agent within the
formulations (Deng et al., 2012). Verreck and co-workers prepared
itraconazole–HPMC solid dispersions using hot melt extrusion
coupled with a DOE. With the addition of DOE, the processing
parameters were fully investigated, including temperature, feed
rate, and screw speed. The amorphous solid dispersion showed
Fig. 4. Dissolution of fenofibrate from the pellet formulations. Pellets were filled
a significant enhanced dissolution rate compared to the physi- into capsules so as to yield 25 mg fenofibrate per capsule.
cal mixture. The formulation was also confirmed to be physically Reprinted with Permission of Informa Healthcare USA, Inc. Drug Development and
and chemically stable during 6 months of storage at different Industrial Pharmacy (Deng et al., 2012), Copyright (2012).
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Polymethacrylate derivatives have also been widely used in melt
extrusion to improve the solubility of water insoluble compounds.
Gryczke et al. utilized Eudragit® EPO with suitable excipients
and ME techniques to produce a fast disintegrating taste-masked
dosage form with improved palatability and superior patient com-
pliance (Gryczke et al., 2011). In this study, Ibuprofen (IBU—a
bitter active) and Eudragit® EPO were processed using ME to pro-
duce a solid dispersion and milled to produce granules. These
granules were blended with superdisintegrants at varying ratios
and directly compressed to produce orally disintegrating tablets,
which had physical properties similar to the marketed Nurofen®
Meltlet. The taste intensity evaluation of the extruded formulations
in healthy human volunteers revealed an excellent taste mask-
ing ability with zero degree of bitterness and smoother mouth
feel in comparison to the moderate roughness levels experienced
with administration of Nurofen® fast dissolving tablets. In addi-
tion, ME tablet formulations with 25% IBU demonstrated similar
release rates as Nurofen® tablets, but 40% IBU/EPO formulations
showed a faster dissolution, which was attributed to a lower talc
concentration in the formulation compared to the 25% IBU/EPO for-
mulation. Overall, the ME formulations with similar disintegration
properties and crushing strengths as that of the marketed for-
mulation had faster drug release rates and could mask the bitter
taste effectively. He et al. evaluated the pharmaceutical perfor-
mance of fenofibrate solid dispersions utilizing Eudragit® E100 as
a hydrophilic carrier (drug/polymer ratio 1:2 and 1:4) (He et al.,
2010). The solid dispersions significantly increased the release
rate of fenofibrate compared to the physical mixture at the same
drug/polymer ratio. It is noteworthy that the formulations exhib-
ited a slower release in 0.1 N HCl with the increase in the percentage
of Eudragit® E100, while a higher release rate in water. This phe-
nomenon was explained by the competition of two factors, pasted
clumping and the solid dispersion effect (negative and positive role
in the determination of dissolution rate, respectively). The authors
also compared the bioavailability of solid dispersions with com-
mercial Lipanthyl® capsules. Eudragit® E100 solid dispersions at a
drug/polymer ratio of 1:4 demonstrated a 177.1% relative bioavail-
ability.
Recently, a novel polyvinyl caprolactam–polyvinyl
acetate–polyethylene glycol graft copolymer, Soluplus® , was
specifically designed and developed for melt extrusion. This
polymer has both hydrophilic and hydrophobic elements, which
therefore enhances the ability of forming a solid solution as well
as increasing solubilization. Therefore, Soluplus® performs very
well as a solubilizing carrier for hot melt extrusion technology. In
addition, Soluplus® provides a wide range for potential candidates,
from low melting to high melting drugs, including heat-sensitive
APIs, due to its comparatively low Tg (70 ◦ C). Linn et al. (2012)
studied the capacity of Soluplus® to increase intestinal absorption
of three BCS II drugs, danazol, fenofibrate and itraconazole. All
of the extrudates containing the three drugs demonstrated sig-
nificant increases in the plasma AUC compared to the crystalline
pure drug or the physical mixture. In addition, the results of
in vitro Caco-2 transport experiments confirmed the strong effect
of Soluplus® on the enhancement of absorption behaviors of the
model drugs. These data demonstrated the much-needed addition
of an effective, extrudable polymer in the pharmaceutical formu-
lators’ toolbox. The utility of Kollicoat® IR, initially developed as
a coating polymer, was evaluated as a carrier in solid dispersions
prepared by hot melt extrusion. Itraconazole–Kollicoat® IR solid
dispersion systems demonstrated instant release properties in
simulated gastric fluid without pepsin (SGFsp ) (Janssens et al.,
2007). Interestingly, supersaturation was maintained as long
as 4 h for formulations containing 15, 20 and 25% itraconazole,
which would be expected to further benefit in vivo absorption.
Although the crystallinity of Kollicoat® IR was found to increase
241
when exposed to higher temperature and shear forces, which
theoretically affect the stability of solid dispersions, Kollicoat® IR
could be alternative carriers for selected drugs in melt extrusion
applications.
Pharmaceutical scientists are also investigating the utilities of
other excipients as carriers in solid dispersions prepared by melt
extrusion. Among those efforts, Kleinebudde and Yano success-
fully extruded indomethacin (IDM) with cyclodextrin at a ratio of
1:1 below the melting point of indomethacin, and the extrudates
demonstrated a significantly higher release rate than the physical
mixture (Yano and Kleinebudde, 2010). Upadhye et al. conducted
another study utilizing cyclodextrins. The researchers prepared a
solid dispersion of 9 -tetrahydrocannabinol hemisuccinate (THC-
HS), an ester prodrug of 9 -tetrahydrocannabinol (THC) using
two types of cyclodextrin: random methylated beta-cyclodextrin
(RAMEB) and 2-hydroxypropyl beta-cyclodextrin (HPBCD). The sol-
ubility of THC-HS was significantly higher in RAMEB compared to
HPBCD. Thus, a combination of ME and cyclodextrin complexation
may be used to enhance solubility, as well as stability of an API
(Upadhye et al., 2010).
Gosau et al. developed a biodegradable poly (lactic-co-glycolic
acid) (PLGA)–gentamicin sulphate (GS) implant, manufactured by
melt extrusion technology. Polyethylene glycol 400 (PEG 400) was
added as a plasticizer as well as a release modifier. The implants
containing 25% GS demonstrated a higher release rate in the ini-
tial state followed by equivalent release profiles compared to the
marked product Septopal® (Blomet, Dramstadt, Germany) (Gosau
and Muller, 2010). In a US patent application by Sherry et al. orally
disintegrating tablets (ODT) of a non-steroidal anti-inflammatory
drug (NSAID), paracetamol were prepared by dry blending the
drugs with sugar alcohols (xylitol, mannitol, sorbitol) and subse-
quently melt extruding the mixture by heating to a temperature
above the melting point of the sugars. The extrudates obtained
after cooling and solidification were milled utilizing a cone mill. The
milled extrudates or granules were mixed with other formulation
components and compressed into tablets. The ODTs obtained by
complete melting of xylitol (low melting sugar alcohol) in the phys-
ical mixture were reported to be more robust compared to those
produced by conventional dry blending processes (Sherry, 2007).
Recently, Poloxamer 407 (generally used as a solubilizing agent)
was investigated as a matrix carrier for a water insoluble, high melt-
ing point compound, Carbamazepine (191–192 ◦ C). In this study,
the formulations containing 10–50% drug load were successfully
extruded in the temperature range of 50–60 ◦ C. All of the devel-
oped formulations demonstrated a significantly higher release rate
compared to a control formulation under non-sink conditions (Lu
et al., 2012).
Kindermann et al. recently fomulated polyelectrolyte com-
plexes of water insoluble acidic drugs and basic polymethacrylates
(EUDRAGIT® E PO) using hot melt extrusion technology. A tailor-
made release profile was achieved with the addition of inorganic
salts (Kindermann et al., 2011). It was observed that the intensi-
ties of stretching vibrations of the vicinal CH2 group at 2771 and
2823 cm−1 coresponding to the non-protonated amine group of
Eudragit® E PO in naproxen-extrudates were significantly lower
than the physical mixture. This phenomenon was attributed to
the drug–polyelectrolyte interaction. Dissolution studies were fur-
ther conducted in non-sink conditions, and the maximum effect of
tailor-made release was achieved when sodium chloride was added
at concentrations of 0.05–0.15 M.
Polymer blends have gained considerable attention from
formulation scientists for the reason that they offer several physico-
chemical attributes to the dosage form as opposed to single
polymer. Kalivoda and co-researchers utilized polymer blends,
including copovidone (COP), polyvinyl caprolactam–polyvinyl
acetate–polyethylene glycol copolymer (PVCL–PVAc–PEG) and
242 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Fig. 5. Dissolution profiles of CBZ, CBZ–NIC cocrystal, solid dispersions prepared by
melting method and the corresponding physical mixtures (n = 3).
Repqcience + Business Media, LLC: Pharmaceutical Research (Liu et al., 2012b), Copy-
right (2012).
hypromellose 2910/5 (HPMC), to increase the solubility of a poorly
water soluble compound fenofibrate (Kalivoda et al., 2012). Solid
dispersions were prepared using hot melt extrusion with varied
polymer ratios in the blends. The dissolution studies were con-
ducted in a non-sink condition containing 500 mL of hydrochloric
acid medium (pH 1.2) with an addition of 0.1% polysorbate 80.
It was observed that the melt extrudates demonstrated a signifi-
cantly faster release rate as compared to pure the fenofibrate or
physical mixture. The release profiles of the developed extrudates
were further compared with marketed formulations, Lipidil and
Lipidil-Ter, and was found to exhibit a superior dissolution profile
than the marketed formulations. Interestingly, with the addition
of PVCL–PVAc–PEG or HPMC into the formulations, the the initial
release rate and the degree of supersaturation were influenced.
A BSC Class II drug with a low Tg (4 ◦ C), 3-methoxy-
1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole was formulated with
polymer blends containing Hydroxypropylmethylcellulose (HPMC,
TC-5R) either with Copovidone (PVP-VA, Kollidon VA64 or
polyvinylpyrrolidone (PVP, PVP-K30) (Sakurai et al., 2012). The Tg
of the formulations was increased with the incoporation of PVP-VA
or PVP which is possibly due to the formation of hydrogen bond-
ing between drug and C O groups in PVP-VA or PVP, indicating
an improvement in the physical stability of the extruded formula-
tions. In vivo absorption studies (Fig. 5) of these formulations were
also performed in male beagle dogs (n = 6). The formulation of drug,
HPMC and PVP at a weight ratio of 1:1:1 demonstarted an increased
solubility and bioavailability as compared to the drug–HPMC solid
dispersion, resulting from a combination effect of the oral absorp-
tion enhancement from HPMC and stability improvement from
PVP. The combination of polymer blends could enhance the prop-
erties of each single polymer in one formulation, which provides
an alternative to formulation development. However, the miscibil-
ity of polymer–polymer and drug–polymer, the phase separation
behavior of drug in the system, the long term stability and any other
properties need to be thoroughly investigated.
5. Characterization
As described previously, solubilization in ME primarily occurs
by amorphous solid dispersion. An amorphous system is a dis-
ordered system with random molecular configuration, in which
individual molecules are randomly oriented with respect to
one another and exist in various conformational states. By
definition, an amorphous material is a solid material without long-
range order characteristics of a crystalline material. Analytical
characterization in amorphous solid dispersion aims at accurately
determining solid-state drug–polymer miscibility, kinetics of solid-
state phase separation and nucleation – crystallization kinetics to
further assists in setting the polymer selection criteria. However,
recently there is growing interest in the development of crystalline
solid dispersion with micro/nano size range of the crystalline drug
dispersed in the amorphous or crystalline matrix for improving
the dissolution of poorly soluble drugs that is devoid of any issues
related to physical stability of drugs in amorphous solid dispersion
(Chatterji et al., 2012; Thommes et al., 2011).
Many attempts have been made to determine the degree of
crystallinity of melt extruded formulations. Undoubtedly, this is
one of the most critical testing steps in the evaluation of a ME
processed amorphous solid dispersion formulation. Selection of
an appropriate/suitable polymer, satisfactory levels of drug load-
ing and efficient and precise process control are key determinants
for successful amorphous formulation development. Any variation
within these parameters can result in incomplete conversion of
a drug from the crystalline to an amorphous state. “Trace” levels
of crystalline drug in amorphous formulations serve as seeds for
recrystallization during in vitro and in vivo dissolution or during
storage, which can further jeopardize the stability of the formula-
tion and hence the entire drug development program.
Determination of residual crystallinity has been an important
analytical characterization aspect for melt extruded amorphous
solid dispersions. Residual crystalline drug in amorphous solid
dispersion can serve as nuclei for recrystallization, leading to desta-
bilization of the dispersion upon storage and ultimately resulting
in a failed formulation strategy (different dissolution and bioavail-
ability profile of the crystalline drug).
While several analytical techniques have been applied for over-
all characterization of melt extruded products, for the purpose
of this review the authors will only focus on techniques provid-
ing valuable information (including quantification) on crystallinity,
or amorphicity of poorly soluble drugs designed as dispersions.
Moreover, an array of such orthogonal techniques as opposed to
a single technique is imperative for successful characterization of
ME dosage forms.
Liu et al. (2012a) described the evaluation of miscibility of
indomethacin and Eudragit® EPO employing thermal, rheological
and spectroscopic analysis. Qi et al. describe successful char-
acterization of melt extruded solid dispersions employing such
orthogonal (thermal, microscopic, and spectroscopic) analytical
methods (Qi et al., 2008, 2010; Qi and Craig, 2010).
5.1. Spectroscopic techniques
5.1.1. X-ray diffraction methods
X-ray diffraction/X-ray powder diffraction (XRD/XRPD) is one
of the most widely used identification technique for crystalline
pharmaceuticals. It is important to note here that XRPD detects the
presence of molecular order (i.e. crystalline state) and not disorder
(amorphous state). The amorphous state is rather implied by the
absence of characteristic Bragg’s peaks and hence the associated
long-range symmetry order (Saleki-Gerhardt et al., 1994).
(i) In the context of melt extrusion, XRD/XRPD finds appli-
cation in two major areas, Product characterization during
design/development (e.g. screening miscibility of amorphous
drug and the polymer, residual amount of crystalline or amor-
phous drug in dispersion etc).
(ii) Assessment of storage stability of melt extruded systems
(e.g. factors influencing recrystallization of amorphous solid
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
dispersions at defined storage conditions, phase separation in
hot-melt extruded solid dispersions).
XRD has been used extensively to study and characterize crys-
tallinity (or amorphicity) of several APIs in melt-extruded systems
(DiNunzio et al., 2010b; Jijun et al., 2011; Kanzer et al., 2010;
Schilling et al., 2010; Sun et al., 2008). XRD has proven to be a
valuable tool to assess the storage stability of amorphous sys-
tems (Albers et al., 2009; Andrews et al., 2010; Maclean et al.,
2011; Prodduturi et al., 2007; Thommes et al., 2011). Co-crystals of
Ibuprofen and Nicotanimide prepared utilizing hot melt extrusion
were evaluated by XRD. In this study it was observed that screws
with intense mixing elements at high temperatures and low mate-
rial residence times resulted in a maximum intensity XRD spectra,
thereby confirming formation of co-crystals (Dhumal et al., 2010).
While, XRPD is undoubtedly an indispensible qualitative identi-
fication tool for crystallinity/amorphicity, quantitative application
is debatable. Using sucrose as a model solid, Saleki-Gerhardt et al.
describe the application of XRD in quantification of disorder in
pharmaceutical drugs. Using predetermined mixtures of crystalline
and amorphous samples, disorder, (or amorphicity) of the sample
was determined. The limit of detection for this approach was about
10% (Saleki-Gerhardt et al., 1994).
Byard et al. (2005) describe the assessment of solid state
nuclear magnetic resonance (ssNMR), XRPD and differential scan-
ning calorimetry (DSC) as methods to quantify amorphous content
in micronized pharmaceutical drug substance. Two XRPD based
approaches (measuring the crystalline peak areas and amorphous
scattering respectively) were used for amorphous content estima-
tion. The alternative approach utilizing amorphous scattering by
XRPD was found to be robust and insensitive to the variations in
crystalline defects and particle size of the material. This approach
established a direct correlation between the amorphous halo inten-
sity and the amorphous drug content in the sample which can be
accurately used for quantification of the later in pharmaceutical
solids (Byard et al., 2005).
While the above-described approaches can accurately deter-
mine % crystallinity (or amorphicity) for pure pharmaceutical solids
(drugs), the presence of polymer in melt extruded systems lim-
its the use of XRPD. An analogous set of standards (with known
crystallinity) can be prepared by mixing pure crystalline and amor-
phous standards of the drug in suitable ratios in a polymer matrix. It
is important to note that such calibration standards would merely
be physical admixtures and rather non-continuous systems. The use
of such two-state calibration models to determine crystallinity in
an amorphous formulation is rather debatable.
Bates and co-workers have described the application of XRPD
method coupled with computation of pair distribution functions
(PDF) to characterize miscibility (between amorphous drug and
the polymer) in amorphous solid dispersions (Bates et al., 2006;
Newman et al., 2008; Rumondor et al., 2009a). Newman et al. stud-
ied three systems representing a miscible, phase separated, and
solid nanosuspension of drug and polymer, respectively. The mis-
cibility (between amorphous drug and the polymer) was assessed
by subjecting the measured XRPD patterns of each system to com-
putational analysis. Such an assessment can be made using DSC;
however, it is limited by certain requirements. The individual Tg
values (amorphous drug and polymer) generally must be about
10 ◦ C apart and the size of the phase separated domains must be
greater than 30 nm for DSC to predict miscibility. The size limita-
tion of domains (30 nm) justifies selecting solid nanosuspension as
one system for this study (Newman et al., 2008).
Rumondor et al. described the use of Partial Least-Squares (PLS)
modeling in quantifying drug crystallinity in felodipine amorphous
solid dispersions by XRPD. They found that PLS analysis signifi-
cantly improved the accuracy and prediction of % drug crystallinity.
243
In comparison to the standard method employing Bragg’s peak area
calculation, PLS analysis significantly improved the accuracy of %
drug crystallinity prediction. Additionally the PLS model enabled
further data analysis, including identification of outliers and non-
linearity, as well as provided insight into factors that were most
important to correlate XRPD diffractograms with % crystallinity of
the drug (Rumondor and Taylor, 2010).
Nollenberger et al. employed the pair distribution function (PDF)
analysis coupled X-ray powder diffraction (XRPD) to determine
local structural order in amorphous melt extrudates of felodipine
with EUDRAGIT® E and EUDRAGIT® E/NE respectively. Extrudates
containing 5% EUDRAGIT® NE demonstrated a faster dissolution
rate and less recrystallization in bio-relevant media. PDF analysis
revealed that addition of EUDRAGIT® NE to EUDRAGIT® E during
extrusion changed the local structure of EUDRAGIT® E, implying
that the local structure is an important drug release criteria in
amorphous systems. Unlike the other standard analytical methods
employed, PDF analysis could detect order differences between the
different polymer extruded systems studied. PDF analysis revealed
that addition of EUDRAGIT® NE to the main component EUDRAGIT®
E during extrusion changed the local structure of EUDRAGIT® E
in a non-additive way (Nollenberger et al., 2009). Taken together,
the use of XRPD coupled with computational methods (PDF) is a
promising means to provide better insights into the local structure
order in amorphous dispersions and explains the improved disso-
lution behavior of drugs from such polymer extrusion products.
5.1.2. IR and Raman spectroscopy
IR and Raman spectroscopy (vibrational spectroscopy tech-
niques), can detect subtle differences in vibrational energy between
crystalline and amorphous states and hence employed in character-
izing amorphous system.Verhoeven et al. utilized Raman analysis
as a qualitative analytical tool to determine sample homogene-
ity. They studied the effect of formulation and process variables
on the release characteristics of metoprolol tartarate from ethyl-
cellulose sustained-release mini-matrices produced by hot-melt
extrusion. Raman anlaysis confirmed that metoprolol tartrate
was homogeneously distributed, independent of screw design
and processing conditions (Verhoeven et al., 2008). Van Eerden-
brugh et al. describe the use of nanoscale-mid-infrared imaging of
phase separation in drug–polymer blends and in binary polymer
blends (Van Eerdenbrugh et al., 2012a,b). The molecular inter-
actions between celecoxib and PVP (Andrews et al., 2010) in
extruded matrices were studied using Fourier transform infrared
spectroscopy (FTIR) and Raman spectroscopy. Zheng et al. (2007)
described the utility of FTIR spectroscopy for characterization of
solid dispersions of Nimodipine prepared by ME. A careful evalu-
ation of the FTIR spectra imply the formation of hydrogen bonds
between secondary amine and hydroxyl groups of drug and poly-
mers (PVP/VA, EPO, HPMC), respectively (Zheng et al., 2007). Albers
et al. demonstrated the utility of FTIR to confirm the amorphous
nature of the poorly water-soluble drug celecoxib in solid disper-
sions of the polymethacrylate carrier Eudragit® E PO (Albers et al.,
2009) prepared by melt extrusion.
Sathigari et al. described the amorphous-state characteriza-
tion of efavirenz (EFV)–polymer hot melt extruded systems. DSC,
XRD, FTIR spectroscopy, and dissolution studies were employed
to characterize the extrudates. The amorphous nature of EFV in
the extrudates was confirmed by XRD and DSC studies. FTIR stud-
ies revealed molecular interaction between the EFV and Plasdone
S-630, attributable to the decreased molecular mobility and stabi-
lization against crystallization (Sathigari et al., 2012).
Attenuated total reflectance Fourier transform infrared (ATR-
FTIR) spectroscopy is a modification of the traditional FTIR to
overcome sensitivity issues. Utilizing ATR-FTIR, Qi et al. described
the non-homogeneous distribution of paracetamol in a Eudragit®
244 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
RSPO matrix. This type of spectroscopy proved to be very valuable
characterization tool for samples extruded at high drug loadings
(Qi et al., 2008).
In the present day, QbD and PAT paradigm, Raman spectroscopy
is being explored as an in-line quality control tool for the assess-
ment of pharmaceutical unit operations (De Beer et al., 2008,
2011). Tumuluri et al. employed Raman spectroscopy as a quanti-
tative and qualitative analysis tool for characterization of hot melt
extruded filmscontaining clotrimazole and ketoprofen as model
APIs. Further, with appropriate modifications, these researchers
demonstrated the effective use of Raman spectroscopy to quantify
API, both off-line and on-line. Raman spectroscopy being sensitive
to changes in drug crystallinity, also finds application in charac-
terizing amorphicity/crystallinity of the model drugs. Since Raman
spectroscopy is sensitive to changes in crystallinity, this methodol-
ogy also provides valuable information on the crytallinity of model
drugs (Tumuluri et al., 2008). Similarly, Saerens et al. demonstrated
the utility of Raman spectroscopy as a PAT tool for inline quantifi-
cation of the drug as well as for the solid-state characterization of
drug–polymer matrix (Saerens et al., 2011).
5.2. Thermal techniques
5.2.1. Differential scanning calorimetry
DSCa sensitive thermal characterization tool is commonly used
to detect phase transformations including melting, miscibility,
glass transitions, and re-crystallization of melt extrudates and ME
based products. Since ME is a thermally intensive process, DSC is
an indispensable tool to follow the thermal events and transforma-
tions occurring in the material during extrusion. In DSC, samples
are heated at a constant rate and the critical temperatures at which
the above-mentioned transitions occur are recorded. DSC subjects
samples to heat at a constant rate, while heat flow is continuously
monitored. The temperatures at which the above-mentioned ther-
mal events occur are recorded.
DSC is used as a primary screening technique to evaluate
drug–polymer miscibility (Schilling et al., 2008), thermal transfor-
mations i.e. melting (Albers et al., 2009; Jijun et al., 2011; Ranzani
et al., 2011; Sun et al., 2008; Thommes et al., 2010), recrystallization
stability (Jijun et al., 2011; Ranzani et al., 2011), glass transitions
(Tg ) (Almeida et al., 2011; Maclean et al., 2011; Miller et al., 2008;
Prodduturi et al., 2007; Yang et al., 2011) and most importantly
to identify the amorphous nature (Andrews et al., 2010; DiNunzio
et al., 2010b; Dong et al., 2008; Mididoddi and Repka, 2007; Miller
et al., 2007; Sun et al., 2008) of the extruded systems (Maclean
et al., 2011). Due to its rapid and high throughput nature, DSC has
been used as a workhorse analytical technique to evaluate differ-
ent quality attributes of melt extruded systems in tandem with
other known characterization methods (Ghebremeskel et al., 2006;
Janssens et al., 2007; Kanaujia et al., 2011; Qi et al., 2008, 2010;
Thommes et al., 2011). DSC has also been used for rapid selection
of crystallization inhibitors (Bruce et al., 2007). Bruce et al. investi-
gated the physical state of hot melt extruded guaifenesin tablets
containing either Acryl-EZE or Eudragit® L100-55. The authors
studied the physicochemical factors influencing crystal growth of
guaifenesin in extrudates utilizing a combination of modulated DSC
and XRPD.
This study also described the interesting application of scan-
ning electron microscopy (SEM) to study the surface morphology
of extrudates and to investigate the recrystallization processes
(particularly the onset of recrystallization) on the surface of the
hot-melt extruded tablets. SEM of the intact and bisected tablets
conclusively demonstrated that crystallization was a rather sur-
face phenomenon and higher for tablets with high amounts of
guaifenesin. SEM revealed absence of crystals on the newly exposed
matrix surface, resulting from bisecting the tablets (for both
Acryl-EZE® - and Eudragit® L100-55 extrudates respectively),
whereas crystal growth was observed after exposure to ambient
storage conditions for 15–30 min. The study further explained sur-
face recrystallization to be possibly due to the lack of restraining
pressure exerted by the polymer matrix at the tablet surface com-
pared to that within the tablet core (Bruce et al., 2007). Additionally
Bruce et al. also determined the effects of varying humidity and
talc content on the surface recrystallization of guaifenesin from
melt-extruded tablets. They observed both presence of talc and
storage at high humidity increased recrystallization of guaifenesin.
However, there was no direct correlation between the amount of
drug recrystallization and the talc concentration or rate of moisture
uptake, making surface recrystallization attributable to heteroge-
neous nucleation (Bruce et al., 2010b). Bruce et al. (2010a) describe
aqueous film coating as a mitigation strategy to reduce sur-
face recrystallization. Film coated guaifenesin-containing tablets
showed prolonged onset time for drug recrystallization. Hypromel-
lose, a hydrophilic polymer (higher solubilization capacity for
guaifenesin), was found to delay crystallization for longer periods of
time in comparison to the more hydrophobic ethylcellulose (lower
solubilization capacity for guaifenesin).
To identify and quantify amorphicity (or crystallinity), the
measurement needs to be completed before the recrystallization
or chemical decomposition of amorphous material has started,
which can be easily accomplished by employing a fast scan rate.
Quantification of sample amorphicity (or crystallinity) requires
measuring the important thermal transition events in the absence
of overlapping events such as sample recrystallization or chemical
decomposition of the sample, which is achievable by employing a
fast scan rate. High speed DSC or Hyper DSC or Fast-Scan DSC is
an extension of the conventional DSC technique, which includes
fast heating rates as high as 500 ◦ C/min. Conventional DSC meas-
ures heat flow as a function of time and temperature, Hyper DSC
allows measurement of this heat flow without overlapping ther-
mal events or sample degradation (Ford and Mann, 2012; Saunders
et al., 2004).
Hyper DSC finds applications in characterization of polymorphs,
determination of amorphicity in crystalline materials and determi-
nation of drug solubility in polymers (formulation characterization)
(Gramaglia et al., 2005; Lappalainen et al., 2006; Mathot et al.,
2002; Saunders et al., 2004). Shortened experimental times and
lower sample volumes are the typical advantages of Hyper-DSC.
Modulated DSC (MDSC) works on the same principle as conven-
tional DSC (Coleman and Craig, 1996) except for the fact that, a
sinusoidal modulation (oscillation) is overlaid on the conventional
linear heating ramp to yield a heating profile in which the aver-
age sample temperature still continuously increases with time but
not in a linear fashion. Specifically, MDSC permits separation of the
total heat flow signal into its thermodynamic (heat capacity (Cp)
component showing melting and glass transition temperatures)
and kinetic components (e.g. crystallization, evaporation, curing).
MDSC therefore allows analysis of mixtures with overlapping ther-
mal events.
Bruce et al. employed MDSC to understand the plasticizing effect
of guaifenesin on Eudragit® L100-55 The glass transition temper-
atures (Tg ) of melt extrudates containing guaifenesin in Eudragit®
L100-55 decreased in a concentration-dependent manner with Tg
of Eudragit® L100-55 being 104.4 ◦ C and that with 20% guaifenesin
being 51 ◦ C. This decrease in the glass transition temperature with
increasing guaifenesin content indicated plasticizing effects of the
drug on polymer thereby favoring the melt-extrusion processing
(Bruce et al., 2007). Janssens et al. employed MDSC to screen
ternary solid dispersions containing itraconazole, PEG 6000, and
HPMC 2910 E5. Their findings suggested that ternary dispersions
with 20% itraconazole, 15/85 of the PEG 6000, and HPMC 2910 E5
respectively, formed completely amorphous system with superior
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
dissolution profile compared to binary, 80/20 of itraconazole/HPMC
2910 E5 solid dispersion (Janssens et al., 2008).
5.2.2. Isothermal microcalorimetry (IC)
Isothermal microcalorimetry is employed for quantification of
amorphous content in the powdered samples (Briggner et al., 1994;
Buckton et al., 1995a,b). IC utilizes the simple concept of mea-
suring heat change accompanying a physical or chemical process.
Measuring such heat change and the associated energy change
accompanying recrystallization of amorphous drugs at a particular
humidity or temperature can lead to quantification of amor-
phous content. While DSC along with its modifications (Hyper-DSC,
MDSC) is a popular calorimetric method for characterizing amor-
phous dispersions it has several limitations, subjecting samples
to excessively high temperatures being one of them. IC as the
name suggests measures the heat energy changes in a sample as
a function of changing humidity at constant temperature. Since
changes in humidity can lead to recrystallization of amorphous
phase, quantification of amorphous component is possible with
IC. IC is extremely sensitive technique and can detect less than 1%
(w/w) amorphous content.
Gaisford has extensively reviewed the applications of isother-
mal microcalorimetry in solid pharmaceuticals (Gaisford, 2012;
O’Neill and Gaisford, 2011). IC can be used to quantify amorphous
drug substances by controlling the relative humidity or relative
vapor pressure in the sample ampoule. This technique, when oper-
ated accurately, can be very sensitive, detecting less than 1% (w/w)
amorphous content. Typically, IC finds application for excipient
compatibility and longer-term stability indicating assays as a com-
plementary technique to DSC.
5.3. Microscopic techniques
Hot stage microscopy (HSM) and SEM are two such flagship
visual techniques used to study the surface morphology of melt
extruded pharmaceuticals (Andrews et al., 2010; Liu et al., 2009;
Mididoddi and Repka, 2007; Miller et al., 2007; Ozkan et al., 2009;
Reitz et al., 2008). Polarized light microscopy is another such impor-
tant microscopic technique employed in combination with several
other analytical techniques to detect crystallinity in amorphous for-
mulation (Gupta et al., 2004; Onoue et al., 2010; Yoo et al., 2009).
Cross-polarized microscope differentiates between crystalline and
amorphous systems by measuring birefringence, moreover amor-
phous materials do not exhibit birefringence.
HSM coupled with polarized light microscopy showed that
paracetamol remained in the crystalline form on mixing with
molten polyethylene glycol (PEG). In addition, while cooling of
the drug–polymer matrix, a decrease in crystallinity of PEG was
observed (Campbell et al., 2008). Ghebremeskel et al. (2006)
describe the use of polarized light microscopy in combination with
other standard analytical techniques to assess the physical stability
of melt extruded solid dispersions upon stress testing.
Liu et al. used hot stage polarized optical microscopy to monitor
the co-crystal formulation. The morphological changes occurring
in drug–polymer blends due to heating (ambient temperature to
200 ◦ C at 10 ◦ C/min) could be recorded using a camera for further
analysis (Liu et al., 2012b).
5.4. Microthermal analysis (Micro-TA)
Microthermal analysis employs a combination of thermal and
microscopy techniques providing the unique advantage of heating
and simultaneously imaging specific regions of the sample at sub-
micron resolution.
Micro-TA is a collective term encompassing a set of techniques
including localized differential thermal analysis (L-DTA), localized
245
thermo mechanical analysis (L-TMA), nanothermal analysis (nano-
TA) and scanning thermal microscopy (SThM). Unlike conventional
thermal techniques, MTA allows localized heating with a probe
at high rates up to 25 ◦ C/s, thus analyzing properties (i.e. melting,
phase separation, recrystallization) in defined local areas without
thermal damage to theentire sample (Craig et al., 2002).
Local thermal analysis (LTA) has been used for the charac-
terization of several multicomponent pharmaceutical systems at
a micron scale (Dai et al., 2009; Harding et al., 2008; Qi et al.,
2010). Six et al. identified phase separation in itraconazole/Eudragit
E100 solid dispersions (prepared by hot-stage extrusion) employ-
ing Micro-TA. The AFM mode was used to visualize the different
phases and LTA to characterize the phases. LTA could identify two
separate and mixed phases of itraconazole and Eudragit® E100,
highlighting the potential of Micro-TA in determining phase sepa-
ration of the solid dispersion, these results independently verified
the MDSC results on phase separation (Six et al., 2003).
Galop et al. describe use of micro-TA to assess drug crystallinity
in solid dispersions. LTA offered a unique advantage to probe
a selected area of the sample, thereby melting the drug locally
without affecting the excipient. Micro-TA provided an insight into
understanding the poor dissolution performance of the solid dis-
persion upon aging (Galop, 2005).
Hasegawa et al. (2004) utilized a combination of electron probe
microanalysis (EPMA) and micro-TA of to investigate the unifor-
mity (homogeneous/heterogeneous dispersion) and physical state
(crystalline/amorphous) of troglitazone in PVP K30 solid disper-
sions.
Qi et al. characterized phase separation in aged hot-melt
extruded solid dispersions of felodipine and Eudragit® E PO
employing a combination of nano-thermal analysis, photothermal
FTIR microspectroscopy coupled with pulsed force mode AFM (Qi
et al., 2011). Qi et al. further classify such analytical methods as
global vs. localized characterization methods. The combined use of
these global and local analysis has been advocated to better under-
stand the phase separation phenomenon in HME solid dispersion
formulations (Qi and Craig, 2010).
5.5. Water vapor sorption
Water vapor sorption, though a resource intensive and tedious
technique, is employed in quantification of amorphous content
in pharmaceutical solids (API’s). Mackin et al. described the util-
ity of dynamic vapor sorption techniques in tandem with IC for
estimation of low levels of amorphous content. Data from both
methods showed excellent agreement (±0.2% amorphous content)
and indicated that the amount of amorphous material generated
is extremely sensitive to small changes in the operating conditions
(Mackin et al., 2002). Grisedale et al. (2011) studied the effects of
milling on the structure and crystallization behavior of salbuta-
mol sulfate using gravimetric vapor sorption analysis in addition
to other standard techniques such as mDSC and XPRD.
Water vapor sorption also finds application as an independent
characterization tool for solid dispersions (Konno and Taylor, 2008;
Marsac et al., 2008). Marsac et al. describe the recrystallization of
nifedipine and felodipine from amorphous molecular level solid
dispersions in the presence of PVP and moisture. The amount
of water sorbed, was measured using isothermal vapor sorption.
Water vapor sorption techniques have also been coupled with spec-
troscopic techniques such as Raman spectroscopy (Feth et al., 2011)
and Near IR spectroscopy (Moran and Buckton, 2009) for charac-
terization of amorphous systems.
Dong et al. (2008) describe the use of water vapor sorption
technique (in addition to several other characterization tools) to
evaluate the solid-state properties of solid dispersions prepared by
melt-extrusion and solvent co-precipitation.
246 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Prodduturi et al. describe the use of rapid dynamic vapor
sorption technique for analysis of films containing hydrox-
ypropyl cellulose and clotrimazole. Films were investigated for
moisture-sorption, mechanical properties, and release character-
istics (Prodduturi et al., 2004).
While each one of the above mentioned characterization meth-
ods have individual limitations, employing a battery of such
methods as opposed to a single method always provides a better
understanding of the system being studied. Finally, the choice of
characterization method primarily depends upon the properties
of the material (physical, thermal and chemical stability etc.)
and the underlying phenomenon being studied (phase separation,
amorphicity, crystallinity etc.). Desired product quality attributes,
confirmatory data needed, and of course, available equipment to
the pharmaceutical scientist are just a few additional consider-
ations prior to design of experiments.
6. Innovation in melt extrusion
6.1. Formation of co-crystals using melt extrusion
Every day there are numerous new chemical entities (NCEs)
being discovered, and most of these face problems of poor
aqueous solubility and lack of adequate physical and chemical
stability. Pharmaceutical scientists have been diligently working
to formulate these drugs in multiple ways by improving their
physico-chemical properties, making them suitable for appropriate
applications. The formation of co-crystals is considered by some
as one of the potential techniques that can achieve the desired
properties of interest, such as improved dissolution rate, stability,
and bioavailability (Smith et al., 2011). Co-crystals are defined as
non-ionic, multi-molecular crystalline complexes. The crystal lat-
tices of co-crystals are mainly composed of an active component
and co-crystal former in a stoichiometric ratio, which are bound
together through non-covalent interactions, primarily hydrogen
bonding. The co-crystals formed might exhibit entirely different
physical properties than the pure components. Many studies have
proved that co-crystals are beneficial in improving the solubility,
stability, bioavailability, and mechanical properties of the active
drug. Co-crystals are mainly formed by solvent-based crystalliza-
tion such as slurry, conversion, evaporation, anti-solvent addition
and solid based techniques such as co-grinding and melt extru-
sion. Of all the above-mentioned techniques, slow evaporation and
co-grinding are the most widely used, however both of these tech-
niques possess scale up limitations. Therefore, in the recent years,
significant progresses have been made to use ME technology to
produce pharmaceutical scalable, solvent free and cost-effective
co-crystals.
Dhumal et al. (2010) have successfully prepared the co-crystals
of Ibuprofen and Nicotinamide (1:1) utilizing melt extrusion tech-
nology. In addition, these researchers have studied the effect of
different process parameters such as screw configuration (low
shear, medium shear and high shear), screw speed (20, 30, and
40 rpm) and extrusion temperature (70, 80 and 90 ◦ C) on forma-
tion of co-crystals and its purity. Preliminary DSC studies have
reported that the eutectic temperature for Ibuprofen and Nico-
tinamide was 74 ◦ C, therefore extrusion temperatures above and
below the eutectic temperature were selected to study their effect
on co-crystallization. XRPD and DSC studies were carried out to
characterize the crystallinity of the final products produced from
ME. The characteristic XRPD peaks of Ibuprofen and co-crystals
of IBU:NIC (1:1) was found to be at 2 = 6◦ and 3.1◦ , respectively.
The formulations extruded at temperatures above the eutectic
temperature (80 and 90 ◦ C) were found to have high co-crystal
purity. In addition, at the studied temperatures above the eutec-
tic temperature, screw configuration exhibited a major role in the
co-crystal formation and its purity. Residence time decreases as
the screw speed increases, therefore the co-crystals produced at
slower speed demonstrated higher co-crystal purity than those
produced at higher screw speeds. Even though both the batches
of co-crystals produced at 80 ◦ C and 90 ◦ C were above the eutec-
tic temperature, the co-crystal produced at 90 ◦ C showed higher
purity than that at 80 ◦ C. Of all the formulations, the co-crystals pro-
duced at high shear, higher temperature (90 ◦ C) and lower screw
speed demonstrated pure co-crystals with no traces of un-reacted
components. Thus, the authors further studied dissolution and sta-
bility on the co-crystals with high purity. The dissolution studies
indicated that the co-crystals showed improved release profiles
compared to pure Ibuprofen, micronized Ibuprofen, and the phys-
ical mixture of Ibuprofen with Nicotinamide. In addition, these
co-crystals were found to be physically stable for up to 6 months
when stored at ambient conditions.
In another study, Liu et al., investigated the in situ formation
of co-crystals in a single-step, utilizing ME technology, in order to
achieve minimal thermal degradation of the active by extruding
the heat sensitive drugs at lower processing temperatures. In this
study, Carbamazepine (CBZ) and Nicotinamide were used as a
model drug and co-crystal former, respectively, while polyvinylpy-
rolidone/vinylacetate (PVP/VA 64), Soluplus® and HPMC were used
as different carrier matrices. The active, co-former and the poly-
meric matrix were mixed together and fed through the extruder
to obtain a solid dispersion with in situ co-crystallization of API
during the process (Liu et al., 2012b).
The authors noticed the possibility of the drug co-crystallization
with Nicotinamide in PVP/VA 64 matrices during DSC character-
ization of the drug–polymer physical mixtures. The hot-stage
microscopy studies revealed that the co-crystals were formed
completely in situ during the extrusion process, in both Soluplus®
and PVP/VA 64 matrices (a single melting point lower than the
API); however, only partial co-crystallization occurred in HPMC
matrices which was evident with melting of crystals at both, 165 ◦ C
(melting temperature of co-crystal) and 190 ◦ C (melting tempera-
ture of Carbamazepine). These results were also confirmatory with
FTIR and XRD data, which further demonstrated that co-crystal
formation, is instantaneous during melt extrusion processing in
PVP/VA 64 matrices. In addition, dissolution data in PVP/VA 64
matrix revealed that the release from co-crystals was relatively
faster than compared to the pure API. The drug release from the
physical mixtures and the drug–polymer melt extrudates was less
than 80% in 2 h, and about 100% in 1 h, respectively, while the
solid dispersion containing API-Nicotinamide-PVP/VA64 released
100% API in just 20 min (Fig. 6), demonstrating the influence of
Nicotinamide as a hydrotropic agent, and its formation of
co-crystals simultaneously during the extrusion process. Similar
dissolution results were observed for the extrudates formed from
Soluplus® and HPMC matrices. Overall, the melting point of the
API was drastically reduced due to the formation of the co-crystal,
which helped in extruding the drug incorporated polymeric solid
dispersions at lower temperatures. The processing temperatures
could also be adjusted based on choice of the co-former employed
during co-crystallization; however, the effect of co-former on
drug re-crystallization, physical stability, moisture sorption prop-
erties, as well as other parameters, should be considered for the
production of a stable formulation.
A few examples of co-crystal complexes that were successfully
formed utilizing ME technology are Ibuprofen–Nicotinamide
(Dhumal et al., 2010). Daurio et al. (2011) describe twin-screw
extrusion as an effective, environment-friendly, and scalable
method for producing co-crystals of Caffeine-Oxalic acid, Nic-
otinamide trans Cinnamic acid, Carbamazepine-Saccharin, and
Theophylline-Citric acid. The authors identified this neat, and
liquid-assisted melt extrusion technique as a viable alternative
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252 247

Fig. 6. Blood concentration of the drug after oral administration of solid dispersions
(1:1, w/w drug:polymer) with PVP-VA (䊉), PVP () and HPMC (). Mean and S.E. of
six animals. Each solid dispersion contained to 100 mg of the drug.
Reprinted with Permission of The Pharmaceutical Society of Japan: Chemical and
Pharmaceutical Bulletin (Sakurai et al., 2012), Copyright (2012).
to the solution crystallization for formation of in situ co-crystals,
where the temperature and the extent of mixing were indicated
as the primary parameters that influenced co-crystals formation
(Daurio et al., 2011).
6.2. Fusion of solvent evaporation/spray drying techniques with
melt extrusion
As mentioned previously, bioavailability of poorly soluble drugs
can be enhanced by converting the active pharmaceutical ingre-
dients (APIs) into a high-energy amorphous state. However, a
problematic issue is retaining their high-energy states for longer
periods of time to improve dissolution rate, and/or bioavailabil-
ity, which could be due to supersaturated levels of API, and higher
mobility at the molecular level. The most common method of pre-
serving this high-energy state is to stabilize kinetically the drug
substance throughout the product’s shelf life. Several factors such
as glass transition temperature of the amorphous product formed,
viscosity of the melt, storage temperature of the product, plas-
ticization of the matrix and atmospheric moisture could greatly
influence the stability of the amorphous dosage forms. One of the
common approaches identified to protect and physically stabilize
the amorphous solids from their re-crystallization tendency is to
disperse the material in the polymeric carriers using melt extrusion.
However, this process requires higher processing temperatures
especially where the melting point of the API is higher, which could
potentially degrade both the API and the carrier matrix. For thermo-
sensitive drugs, to perform the extrusion process at relatively lower
temperatures, the process may be combined with other techniques
such as rotary evaporation, spray-drying and spray-granulation,
where the API is initially converted into an amorphous form (to
lower the glass transition temperature). This amorphous API is later
extruded using a suitable polymeric carrier matrix by employing
lower processing temperatures to form a stable solid dispersion.
In a research, study performed by Lakshman et al. (2008) a crys-
talline, high melting NCE with poor water solubility was utilized
as a model drug and the authors formulated a stable solid dis-
persion using a combination of solvent evaporation with ME. The
authors produced an amorphous drug utilizing a solvent evapora-
tion technique, where the drug was dissolved in a large amount
of organic solvent and eventually evaporated and dried. The pro-
duced API form had demonstrated a glass transition temperature of
around 125 ◦ C, which is much lower than the original API melting
point (170 ◦ C). In order to form a stable solid dispersion, a suit-
able carrier (PVP K30) was identified using hot-stage microscopy
that demonstrated complete miscibility of the API in the poly-
meric matrix over the temperatures used during extrusion. The
polymeric solid dispersions formed did not demonstrate drug
re-crystallization throughout the length of stability study, how-
ever, phase separation of drug-rich and polymer-rich phases were
noticed (two glass transition temperatures were observed) after
6 months, especially at accelerated conditions. This issue could
be potentially lowered or avoided by utilizing proper packaging
conditions.
Addition of a plasticizer to the formulation lowered the torque
during the melt extrusion process, which minimized the localized
heating of the drug and polymer, further improving the stability and
processability of the solid dispersion. Moreover, the pharmacoki-
netic data also revealed that the bioavailability of the dispersion
was significantly higher in comparison to the formulation with
crystalline drug triturated with Pluronic. In spite of stable formula-
tions being developed in the current study, using such techniques
to produce amorphous APIs prior to ME could pose potential manu-
facturing and scale-up issues due to the requirement of unfriendly
environment organic solvents thereby limiting the use of such
techniques. However, techniques such as lyophillization could be
combined with ME as a potential alternative to overcome these
limitations.
7. Marketed formulations
There are various solid dispersion systems as pharmaceutical
products on the market (Breitenbach, 2002), which include:

Table 2
Currently marketed and developed drug products produced utilizing hot melt extrusion technology (DiNunzio et al., 2012).

Product Indication HME purpose Company

Lacrisert® (Opthalmic Insert) Dry eye syndrome Shaped system Merck

ZoladexTM (Goserelin Acetate Prostate cancer Shaped system AstraZeneca
Injectable Implant)
Implanon® (Etonogestrel Implant) Contraceptive Shaped system Organon
Gris-PEG (Griseofulvin) Anti-fungal Crystalline dispersion Pedinol Pharmacal Inc.
NuvaRing® (Etonogestrel, Ethinyl Contraceptive Shaped system Merck
Estradiol depot system)
Norvir® (Ritonavir) Anti-viral (HIV) Amorphous dispersion Abbott Laboratories
Kaletra® (Ritonavir/Lopinavir) Anti-viral (HIV) Amorphous dispersion Abbott Laboratories
Eucreas® (Vildagliptin/Metformin HCl) Diabetes Melt granulation Novartis
Zithromax® (Azythromycin Anti-biotic Melt congeal Pfizer
enteric-coated multiparticulates)
Orzurdex® (Dexamethasone Macular edema Shaped system Allergan
Implantable Device)
FenoglideTM (Fenofibrate) Dyslipidemia MeltDose® (solid dispersion) Life Cycle Pharma
Anacetrapib (Under Development) Atherosclerosis Amorphous dispersion Merck
Posaconazole (Under Development) Antifungal Amorphous dispersion Merck
248 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252

Griseofulvin–Polyethyleneglycol dispersion (Gris-PEG® marketed

Supercritical anti-solvent (SAS) (Lim et al., 2010; Uzun et al., 2011) overcomes process
by Wander) and Cesamet® , a Nabilone-PVP preparation (marketed
by Lilly). Another formulation of Troglitazone (Rezulin® ) by Parke-

limitations and produces dried composites suitable for subsequent processing.

Davis was earlier on the market, but was withdrawn from the

Residual solvent content, safety concerns; secondary drying process required

US market in 2000 due to toxicology related issues of the active.

Residual solvent in the final product (water content); stability concerns

Apart from these, several commercialized implants containing

Employs volatile organic solvents (process and environmental hazard)

Luteininzing hormone releasing hormone (LHRH) agonists such

Lack of process control, phase separation due to poor cooling rates,

Limited drug/polymer solubilities in supercritical carbon dioxide,

as Goserelin (Zoladex® ), Buserelin (Depot–Profact® ), and devices
such as Implanon® and Nuvaring® are also available in the form

High thermal stress; not suitable for thermolabile materials,

of solid dispersions/solutions. Although there is a huge potential

Material should have optimal thermoplastic properties

of formulating many poorly soluble drugs into solid dispersions

Drug and polymer require a common volatile solvent

Drug and matrix should be compatible and mix well

Phase separation upon storage; potential instability

using melt extrusion for improved bioavailability, to date, few
have been commercialized so far. This, however, is changing and
will continue to do so.

Heat intensive process; thermal instability

Energy intensive manufacturing process

A classic example for a marketed ME pharmaceutical product

High cost, time and energy inefficient,

Congealing due to insufficient drying,
is Meltrex Kaletra® tablets, which was developed by SOLIQSTM

Problem with clogged nozzle heads

(Germany) to improve patient compliance and hence their adher-
ence to the highly active anti-retroviral therapy (Breitenbach,
2006). Kaletra® is a protease-inhibitor combination product, an

High manufacturing cost

important treatment option for patients suffering from HIV, and
each of these tablets consists of 200 mg of Lopinavir and 50 mg
Ritonavir in PVP/VA matrix, as opposed to Kaletra® soft gel
capsules containing 133 mg and 33 mg of Lopinavir and Ritona-
vir, respectively. The application of melt extrusion technology
has turned scientific challenges into patient benefits, reformulat-

Cons
ing a product with many desired attributes: (a) better stability
at room temperature, (b) administration independent of meal
times, and (c) requiring fewer numbers of tablets to be admin-
istered (4 tablets/day) in comparison to 6 soft gel capsules/day
(Breitenbach, 2006). Due to these added benefits, Kaletra® was
granted a fast track approval by U. S. Food and Drug Adminis-

Lower processing temperatures compared to HME and fusion method

Rapid, high purity and high yield, carbon dioxide is safe, inexpensive
tration (FDA) in October 2005, followed by EU approval in July

and commercially available, used for drugs susceptible to hydrolytic

Continuous, rapid, robust, scalable process, can be used to produce

2006. SOLIQSTM has also demonstrated an added advantage of

Continuous, customizable, modular, robust and scalable process

Pros and cons of melt extrusion in comparison to other processing techniques for preparation of solid dispersion.

MeltrexTM technology in producing stable amorphous final dosage

Large scale production equipment available and standardized

Robust and mild production conditions (heat sensitive drugs)
forms, based on years of studies, thus eliminating issues associated
with polymorphism of drug substances, such as stability and/or
degradation-potential advantage over freeze drying

bioavailability.

Amenable to large scale commercial manufacture

In addition to the above product, SOLIQSTM has also devel-
oped a sustained release formulation of Verapamil in polyethylene

Large scale commercial production feasible

glycol–glyceride matrix (Isoptin SRE-240) that was the first directly
Simple laboratory processing equipment

Controlled high temperature processing

shaped ME product on the market, as well as a fast-onset Ibuprofen

Traditional, simple very first method

system (Andrews et al., 2010). Also, in 2010 Abbott announced that

the U. S. FDA approved a new thermally stable tablet formulation
micro and nano particulates
of the protease inhibitor Norvir® (Ritonavir). This new formulation
does not require refrigeration and can be stored at room tempera-
Solvent free processing

ture making it more convenient for patients.

Solvent free method

Few formulations that are currently under development from

Pharmaceutical companies such as Merck and Particle sciences
include Anacetrapib, Posaconazole (antifungal), Dapivirine (anti-
viral) and Maraviroc (anti-viral) etc. Anacetrapib, a cholesteryl ester
Pros

transfer protein (CETP) inhibitor, is currently being developed for

atherosclerosis by Merck as a melt extruded formulation contain-
ing Kollidon® VA 64 as a polymer matrix with vitamin E TPGS
and additional surfactant materials (DiNunzio et al., 2012). The
data from the pre-clinical studies in Rhesus monkeys demonstrated
Supercritical fluid processing (SFP)

superior bioavailability and reduced variability of the Anacetrapib

melt extruded formulation in comparison to its spray-dried disper-
sion. This ME formulation is currently being evaluated in Phase-III
clinical trials, and the early results from Phase IIb (efficacy and tol-
erability) that was presented at the American Heart Association
meeting in 2010 demonstrated that a 100 mg dosage decreased
Fusion method

Melt extrusion
Freeze drying

LDL by 36% and increased HDL by 138%, with no association with

Spray drying
Technique

increased cardiovascular disease events (Cannon et al., 2010). Addi-

tionally, Posaconazole is another solid dispersion product, which is
Table 3

being developed by Merck. The active is dispersed in a matrix of

hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
the eutectic mixture formed allows reduced temperatures for pro-
duction of the product using a twin-screw co-rotating extruder,
solubilizing the active in the polymer matrix (DiNunzio et al., 2012).
The obtained extrudates are then milled, mixed with extra-granular
materials, and compressed into tablets containing a 100 mg dose. A
comparative pharmacokinetic crossover study in healthy human
volunteers with marketed Noxafil® demonstrated a significant
improvement in oral bioavailability with reduced variation in fast
and fed states (minimal food effects) as well as reduced inter-
patient variability, allowing for improved product attributes of the
formulation.
There are already several pharmaceutical products on the mar-
ket either currently being manufactured or under development
using melt extrusion technology (Table 2), which demonstrates
its production feasibility and scaling ability for commercialization.
Many multi-national companies have been investing and perform-
ing extensive research with melt extrusion and are adopting this
relatively new technique of producing and commercializing solid
dispersions in recent years.
8. Comparison of different solid dispersion techniques
Table 3 summarizes the pros and cons of Melt extrusion tech-
nology in comparison to other processing techniques used for
preparation of solid dispersions. It should be emphasized that no
single processing technique or technology may provide the nec-
essary means to desirable product quality attributes and hence
the successful development and commercialization of a particular
pharmaceutical dosage form or device.
9. Conclusion
Over the last two decades, the pharmaceutical industry has
made significant progress in the drug discovery and design front
that has yielded a vast number of potential drug candidates
with poor or limited solubility and hence limited bioavailability.
Melt extrusion as a manufacturing technique has been success-
fully adapted in the mainstream pharmaceutical industry and has
emerged as an innovative alternative in the drug-product develop-
ment arena particularly for solubility enhancement.
Melt extrusion will continue to be a highly sought alternative
since there is a continuous need for innovative drug products,
intellectual property protection and integrated, yet cost-effective
manufacturing platforms. While melt extrusion might mistakenly
be perceived to be a recent development in the pharmaceutical
industry, the first marketed melt extruded drug product using
these techniques was on the market in 1981 with several prod-
ucts developed thereafter or under development over the last 30
years. It is noteworthy that several products developed by melt
extrusion have successfully replaced conventional drug delivery
systems.
In conclusion, producing solid dispersions by melt extrusion
techniques has become a popular means for improving solubil-
ity and hence bioavailability of poorly soluble APIs. A successfully
developed melt extrusion based product is defined by several
formulation, equipment, design, and processing factors. Care-
ful assessment and control of each of these factors and their
interplay governs key product quality attributes. Finally, as poten-
tial new drug candidates (poorly soluble) continue to be discovered,
there will be an existing requirement of advanced formulation
development technologies. Melt extrusion will continue to be at
the forefront of such formulation technologies and enable the
commercialization of drug products, as well as unique platform
technologies.
249
Acknowledgments
This study was supported by HRSA/OFAM/DGMO grant
#D1DHP20294. The authors would also like to thank the Pii Center
for Pharmaceutical Technology for its support of this project.
References
Abu-Diak, O.A., Jones, D.S., Andrews, G.P., 2012. Understanding the perfor-
mance of melt-extruded poly(ethylene oxide)-bicalutamide solid dispersions:
characterisation of microstructural properties using thermal, spectroscopic and
drug release methods. J. Pharm. Sci. 101, 200–213.
Albers, J., Alles, R., Matthee, K., Knop, K., Nahrup, J.S., Kleinebudde, P., 2009. Mech-
anism of drug release from polymethacrylate-based extrudates and milled
strands prepared by hot-melt extrusion. Eur. J. Pharm. Biopharm. 71, 387–394.
Almeida, A., Possemiers, S., Boone, M.N., De Beer, T., Quinten, T., Van Hoorebeke, L.,
Remon, J.P., Vervaet, C., 2011. Ethylene vinyl acetate as matrix for oral sustained
release dosage forms produced via hot-melt extrusion. Eur. J. Pharm. Biopharm.
77, 297–305.
Andrews, G.P., Abu-Diak, O., Kusmanto, F., Hornsby, P., Hui, Z., Jones, D.S., 2010.
Physicochemical characterization and drug-release properties of celecoxib hot-
melt extruded glass solutions. J. Pharm. Pharmacol. 62, 1580–1590.
Bates, S., Zografi, G., Engers, D., Morris, K., Crowley, K., Newman, A., 2006. Analysis
of amorphous and nanocrystalline solids from their X-ray diffraction patterns.
Pharm. Res. 23, 2333–2349.
Bhattacharya, S., Suryanarayanan, R., 2009. Local mobility in amorphous
pharmaceuticals—characterization and implications on stability. J. Pharm. Sci.
98, 2935–2953.
Breitenbach, J., 2002. Melt extrusion: from process to drug delivery technology. Eur.
J. Pharm. Biopharm. 54, 107–117.
Breitenbach, J.r., 2006. Melt extrusion can bring new benefits to HIV therapy: the
example of Kaletra® tablets. Am. J. Drug Deliv. 4, 61–64.
Briggner, L.-E., Buckton, G., Bystrom, K., Darcy, P., 1994. The use of isothermal
microcalorimetry in the study of changes in crystallinity induced during the
processing of powders. Int. J. Pharm. 105, 125–135.
Bruce, C., Fegely, K.A., Rajabi-Siahboomi, A.R., McGinity, J.W., 2007. Crystal growth
formation in melt extrudates. Int. J. Pharm. 341, 162–172.
Bruce, C.D., Fegely, K.A., Rajabi-Siahboomi, A.R., McGinity, J.W., 2010a. Aqueous film
coating to reduce recrystallization of guaifenesin from hot-melt extruded acrylic
matrices. Drug Dev. Ind. Pharm. 36, 218–226.
Bruce, C.D., Fegely, K.A., Rajabi-Siahboomi, A.R., McGinity, J.W., 2010b. The influ-
ence of heterogeneous nucleation on the surface crystallization of guaifenesin
from melt extrudates containing Eudragit L10055 or Acryl-EZE. Eur. J. Pharm.
Biopharm. 75, 71–78.
Buckton, G., Darcy, P., Greenleaf, D., Holbrook, P., 1995a. The use of isothermal
microcalorimetry in the study of changes in crystallinity of spray-dried salbu-
tamol sulphate. Int. J. Pharm. 116, 113–118.
Buckton, G., Darcy, P., Mackellar, A.J., 1995b. The use of isothermal microcalorimetry
in the study of small degrees of amorphous content of powders. Int. J. Pharm.
117, 253–256.
Byard, S.J., Jackson, S.L., Smail, A., Bauer, M., Apperley, D.C., 2005. Studies on the
crystallinity of a pharmaceutical development drug substance. J. Pharm. Sci. 94,
1321–1335.
Campbell, K., Craig, D.Q., McNally, T., 2008. Poly(ethylene glycol) layered silicate
nanocomposites for retarded drug release prepared by hot-melt extrusion. Int.
J. Pharm. 363, 126–131.
Cannon, C.P., Shah, S., Dansky, H.M., Davidson, M., Brinton, E.A., Gotto, A.M.,
Stepanavage, M., Liu, S.X., Gibbons, P., Ashraf, T.B., Zafarino, J., Mitchel, Y., Barter,
P., 2010. Safety of anacetrapib in patients with or at high risk for coronary heart
disease. N. Engl. J. Med. 363, 2406–2415.
Chatterji, A., D.D., Miller, D.A., Sandhu, H., Shah, N., 2012. Process for controlled crys-
tallization of an active pharmaceutical ingredient from supercooled liquid state
by hot melt extrusion. In: Office, U.S.P.a.T. (Ed.). United States, www.uspto.gov,
WO/2012/110469.
Chiou, W.L., Riegelman, S., 1971. Pharmaceutical applications of solid dispersion
systems. J. Pharm. Sci. 60, 1281–1302.
Chokshi, R.J., Sandhu, H.K., Iyer, R.M., Shah, N.H., Malick, A.W., Zia, H., 2005. Charac-
terization of physico-mechanical properties of indomethacin and polymers to
assess their suitability for hot-melt extrusion processs as a means to manufac-
ture solid dispersion/solution. J. Pharm. Sci. 94, 2463–2474.
Coleman, N.J., Craig, D.Q.M., 1996. Modulated temperature differential scanning
calorimetry. A novel approach to pharmaceutical thermal analysis. Int. J. Pharm.
135, 13–29.
Craig, D.Q., Kett, V.L., Andrews, C.S., Royall, P.G., 2002. Pharmaceutical applications
of micro-thermal analysis. J. Pharm. Sci. 91, 1201–1213.
Crowley, M.M., Zhang, F., Repka, M.A., Thumma, S., Upadhye, S.B., Battu, S.K., McGin-
ity, J.W., Martin, C., 2007. Pharmaceutical applications of hot-melt extrusion:
part I. Drug Dev. Ind. Pharm. 33, 909–926.
Dai, X., Reading, M., Craig, D.Q., 2009. Mapping amorphous material on a partially
crystalline surface: nanothermal analysis for simultaneous characterisation and
imaging of lactose compacts. J. Pharm. Sci. 98, 1499–1510.
Daurio, D., Medina, C., Saw, R., Nagapudi, K., Alvarez-Núñez, F., 2011. Application of
twin screw extrusion in the manufacture of cocrystals, part I: four case studies.
Pharmaceutics 3, 582–600.
250 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
De Beer, T., Burggraeve, A., Fonteyne, M., Saerens, L., Remon, J.P., Vervaet, C., 2011.
Near infrared and Raman spectroscopy for the in-process monitoring of phar-
maceutical production processes. Int. J. Pharm. 417, 32–47.
De Beer, T.R., Bodson, C., Dejaegher, B., Walczak, B., Vercruysse, P., Burggraeve, A.,
Lemos, A., Delattre, L., Heyden, Y.V., Remon, J.P., Vervaet, C., Baeyens, W.R., 2008.
Raman spectroscopy as a process analytical technology (PAT) tool for the in-line
monitoring and understanding of a powder blending process. J. Pharm. Biomed.
Anal. 48, 772–779.
Deng, W., Singh, A., Shah, S., Mohammed, N., Jo, S., Majumdar, S., Pinto, E., Tewari, D.,
Durig, T., Repka, M.A., 2012. Stabilization of fenofibrate in low molecular weight
hydroxypropylcellulose matrices produced by hot melt extrusion. Drug Dev. Ind.
Pharm., http://dx.doi.org/10.3109/03639045.2012.679280.
Dhumal, R.S., Kelly, A.L., York, P., Coates, P.D., Paradkar, A., 2010. Cocrystaliza-
tion and simultaneous agglomeration using hot melt extrusion. Pharm. Res. 27,
2725–2733.
Dierickx, L., Saerens, L., Almeida, A., De Beer, T., Remon, J.P., Vervaet, C., 2012.
Co-extrusion as manufacturing technique for fixed-dose combination mini-
matrices. Eur. J. Pharm. Biopharm. 81, 683–689.
DiNunzio, J.C., Martin, Z.F.C., Mcginity, J.W., 2012. Melt extrusion. In: Williams III,
R.O., Watts, A.B., Miller, D.A. (Eds.), Formulating Poorly Water Soluble Drugs.
Springer, New York, NY, pp. 311–362.
Dinunzio, J.C., Brough, C., Hughey, J.R., Miller, D.A., Williams 3rd, R.O., McGinity,
J.W., 2010a. Fusion production of solid dispersions containing a heat-sensitive
active ingredient by hot melt extrusion and Kinetisol dispersing. Eur. J. Pharm.
Biopharm. 74, 340–351.
DiNunzio, J.C., Brough, C., Miller, D.A., Williams 3rd, R.O., McGinity, J.W., 2010b.
Fusion processing of itraconazole solid dispersions by kinetisol dispers-
ing: a comparative study to hot melt extrusion. J. Pharm. Sci. 99, 1239–
1253.
Dong, Z., Chatterji, A., Sandhu, H., Choi, D.S., Chokshi, H., Shah, N., 2008. Evaluation
of solid state properties of solid dispersions prepared by hot-melt extrusion and
solvent co-precipitation. Int. J. Pharm. 355, 141–149.
Dreiblatt, A., 2003. Process design. In: Ghebre-Sellassie, I., Martin, C. (Eds.), Pharma-
ceutical Extrusion Technology. Marcel Dekker, Inc., New York, pp. 153–169.
Feng, J., Xu, L., Gao, R., Luo, Y., Tang, X., 2011. Evaluation of polymer carriers with
regard to the bioavailability enhancement of bifendate solid dispersions pre-
pared by hot-melt extrusion. Drug Dev. Ind. Pharm. 38 (6), 735–743.
Feth, M.P., Jurascheck, J., Spitzenberg, M., Dillenz, J., Bertele, G., Stark, H., 2011.
New technology for the investigation of water vapor sorption-induced crys-
tallographic form transformations of chemical compounds: a water vapor
sorption gravimetry-dispersive Raman spectroscopy coupling. J. Pharm. Sci. 100,
1080–1092.
Food and Drug Administration Process Analytical Technology Initiative, G.f.I., 2004.
In: Administration, U.S.D.o.H.a.H.S.F.a.D. (Ed.), Process Analytical Technology
Initiative, Guidance for Industry, PAT—A Framework for Innovative Pharmaceu-
tical Development, Manufacturing and Quality Assurance.
Food and Drug Administration Quality systems Approach to Pharmaceutical cGMP
Regulations, G.f.I., 2006. In: Administration, U.S.D.o.H.a.H.S.F.a.D. (Ed.)., Quality
Systems Approach to Pharmaceutical cGMP Regulations, Guidance for Industry.
Ford, J.L., Mann, T.E., 2012. Fast-Scan DSC and its role in pharmaceutical physical
form characterisation and selection. Adv. Drug Deliv. Rev. 64, 422–430.
Forster, A., Hempenstall, J., Tucker Rades, T., 2001a. The potential of small-scale
fusion experiments and the Gordon–Taylor equation to predict the suitability
of drug/polymer blends for melt extrusion. Drug Dev. Ind. Pharm. 27, 549–560.
Forster, A., Hempenstall, J., Tucker, I., Rades, T., 2001b. Selection of excipients for
melt extrusion with two poorly water-soluble drugs by solubility parameter
calculation and thermal analysis. Int. J. Pharm. 226, 147–161.
Fu, J., Zhang, L., Guan, T., Tang, X., He, H., 2010. Stable nimodipine tablets with
high bioavailability containing NM-SD prepared by hot-melt extrusion. Powder
Technol. 204, 214–221.
Gaisford, S., 2012. Isothermal microcalorimetry for quantifying amorphous content
in processed pharmaceuticals. Adv. Drug Deliv. Rev. 64, 431–439.
Galop, M., 2005. Study of pharmaceutical solid dispersions by microthermal analysis.
Pharm. Res. 22, 293–302.
Ghebremeskel, A.N., Vemavarapu, C., Lodaya, M., 2006. Use of surfactants as plas-
ticizers in preparing solid dispersions of poorly soluble API: stability testing of
selected solid dispersions. Pharm. Res. 23, 1928–1936.
Ghosh, I., Snyder, J., Vippagunta, R., Alvine, M., Vakil, R., Tong, W.Q., Vippagunta, S.,
2011. Comparison of HPMC based polymers performance as carriers for manu-
facture of solid dispersions using the melt extruder. Int. J. Pharm. 419, 12–19.
Gnoth, S., Jenzsch, M., Simutis, R., Lubbert, A., 2007. Process analytical technol-
ogy (PAT): batch-to-batch reproducibility of fermentation processes by robust
process operational design and control. J. Biotechnol. 132, 180–186.
Gosau, M., Muller, B.W., 2010. Release of gentamicin sulphate from biodegradable
PLGA-implants produced by hot melt extrusion. Pharmazie 65, 487–492.
Gramaglia, D., Conway, B.R., Kett, V.L., Malcolm, R.K., Batchelor, H.K., 2005. High
speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a
solid or semi-solid matrix. Int. J. Pharm. 301, 1–5.
Greenhalgh, D.J., Williams, A.C., Timmins, P., York, P., 1999. Solubility parameters as
predictors of miscibility in solid dispersions. J. Pharm. Sci. 88, 1182–1190.
Grisedale, L.C., Jamieson, M.J., Belton, P.S., Barker, S.A., Craig, D.Q., 2011. Charac-
terization and quantification of amorphous material in milled and spray-dried
salbutamol sulfate: a comparison of thermal, spectroscopic, and water vapor
sorption approaches. J. Pharm. Sci. 100, 3114–3129.
Gryczke, A., Schminke, S., Maniruzzaman, M., Beck, J., Douroumis, D., 2011. Develop-
ment and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen
granules prepared by hot melt extrusion. Colloids Surf. B: Biointerfaces 86,
275–284.
Grzybowska, K., Paluch, M., Grzybowski, A., Wojnarowska, Z., Hawelek, L.,
Kolodziejczyk, K., Ngai, K.L., 2010. Molecular dynamics and physical stabil-
ity of amorphous anti-inflammatory drug: celecoxib. J. Phys. Chem. B 114,
12792–12801.
Guns, S., Mathot, V., Martens, J.A., Van den Mooter, G., 2012. Upscaling of the hot-melt
extrusion process: comparison between laboratory scale and pilot scale pro-
duction of solid dispersions with miconazole and Kollicoat(R) IR. Eur. J. Pharm.
Biopharm. 81, 674–682.
Gupta, P., Kakumanu, V.K., Bansal, A.K., 2004. Stability and solubility of celecoxib-PVP
amorphous dispersions: a molecular perspective. Pharm. Res. 21, 1762–1769.
Hancock, B.C., Shamblin, S.L., Zografi, G., 1995. Molecular mobility of amorphous
pharmaceutical solids below their glass transition temperatures. Pharm. Res.
12, 799–806.
Harding, L., Qi, S., Hill, G., Reading, M., Craig, D.Q., 2008. The development
of microthermal analysis and photothermal microspectroscopy as novel
approaches to drug-excipient compatibility studies. Int. J. Pharm. 354, 149–157.
Hasegawa, S., Hamaura, T., Furuyama, N., Horikawa, S., Kusai, A., Yonemochi, E., Ter-
ada, K., 2004. Uniformity and physical states of troglitazone in solid dispersions
determined by electron probe microanalysis and microthermal analysis. Int. J.
Pharm. 280, 39–46.
He, H., Yang, R., Tang, X., 2010. In vitro and in vivo evaluation of fenofibrate solid
dispersion prepared by hot-melt extrusion. Drug Dev. Ind. Pharm. 36, 681–687.
Hildebrand, J., Scott, R., 1950. Solubility of Non-Electrolytes, 3rd ed. Reinhold, New
York.
Hughey, J.R., DiNunzio, J.C., Bennett, R.C., Brough, C., Miller, D.A., Ma, H., Williams 3rd,
R.O., McGinity, J.W., 2010. Dissolution enhancement of a drug exhibiting thermal
and acidic decomposition characteristics by fusion processing: a comparative
study of hot melt extrusion and KinetiSol dispersing. AAPS PharmSciTech 11,
760–774.
Janssens, S., de Armas, H.N., Remon, J.P., Van den Mooter, G., 2007. The use of a
new hydrophilic polymer, Kollicoat IR, in the formulation of solid dispersions of
Itraconazole. Eur. J. Pharm. Sci. 30, 288–294.
Janssens, S., de Armas, H.N., Roberts, C.J., Van den Mooter, G., 2008. Characterization
of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5. J.
Pharm. Sci. 97, 2110–2120.
Janssens, S., Van den Mooter, G., 2009. Review: physical chemistry of solid disper-
sions. J. Pharm. Pharmacol. 61, 1571–1586.
Jijun, F., Lishuang, X., Xiaoli, W., Shu, Z., Xiaoguang, T., Xingna, Z., Haibing, H., Xing,
T., 2011. Nimodipine (NM) tablets with high dissolution containing NM solid
dispersions prepared by hot-melt extrusion. Drug Dev. Ind. Pharm. 0, 1–11.
Kakumanu, V.K., Bansal, A.K., 2002. Enthalpy relaxation studies of celecoxib amor-
phous mixtures. Pharm. Res. 19, 1873–1878.
Kalivoda, A., Fischbach, M., Kleinebudde, P., 2012. Application of mixtures of
polymeric carriers for dissolution enhancement of fenofibrate using hot-melt
extrusion. Int. J. Pharm. 429, 58–68.
Kanaujia, P., Lau, G., Ng, W.K., Widjaja, E., Schreyer, M., Hanefeld, A., Fischbach, M.,
Saal, C., Maio, M., Tan, R.B., 2011. Investigating the effect of moisture protection
on solid-state stability and dissolution of fenofibrate and ketoconazole solid
dispersions using PXRD, HSDSC and Raman microscopy. Drug Dev. Ind. Pharm.
37 (9), 1026–1035.
Kanzer, J., Tho, I., Flaten, G.E., Magerlein, M., Holig, P., Fricker, G., Brandl, M., 2010. In-
vitro permeability screening of melt extrudate formulations containing poorly
water-soluble drug compounds using the phospholipid vesicle-based barrier. J.
Pharm. Pharmacol. 62, 1591–1598.
Khougaz, K., Clas, S.D., 2000. Crystallization inhibition in solid dispersions of MK-
0591 and poly(vinylpyrrolidone) polymers. J. Pharm. Sci. 89, 1325–1334.
Kindermann, C., Matthee, K., Strohmeyer, J., Sievert, F., Breitkreutz, J., 2011. Tailor-
made release triggering from hot-melt extruded complexes of basic polyelec-
trolyte and poorly water-soluble drugs. Eur. J. Pharm. Biopharm. 79, 372–381.
Konno, H., Taylor, L.S., 2006. Influence of different polymers on the crystalliza-
tion tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 95,
2692–2705.
Konno, H., Taylor, L.S., 2008. Ability of different polymers to inhibit the crystallization
of amorphous felodipine in the presence of moisture. Pharm. Res. 25, 969–978.
Lakshman, J.P., Cao, Y., Kowalski, J., Serajuddin, A.T., 2008. Application of melt extru-
sion in the development of a physically and chemically stable high-energy
amorphous solid dispersion of a poorly water-soluble drug. Mol. Pharm. 5,
994–1002.
Lappalainen, M., Pitkanen, I., Harjunen, P., 2006. Quantification of low levels of
amorphous content in sucrose by hyperDSC. Int. J. Pharm. 307, 150–155.
Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid
dispersions. Eur. J. Pharm. Biopharm. 50, 47–60.
Lim, R.T.Y., Ng, W.K., Tan, R.B.H., 2010. Amorphization of pharmaceutical compound
by co-precipitation using supercritical anti-solvent (SAS) process (Part I). The
Journal of Supercritical Fluids 53, 179–184.
Linn, M., Collnot, E.M., Djuric, D., Hempel, K., Fabian, E., Kolter, K., Lehr, C.M., 2012.
Soluplus(R) as an effective absorption enhancer of poorly soluble drugs in vitro
and in vivo. Eur. J. Pharm. Sci. 45, 336–343.
Liu, H., Wang, P., Zhang, X., Shen, F., Gogos, C.G., 2010. Effects of extrusion process
parameters on the dissolution behavior of indomethacin in Eudragit E PO solid
dispersions. Int. J. Pharm. 383, 161–169.
Liu, H., Zhang, X., Suwardie, H., Wang, P., Gogos, C.G., 2012a. Miscibility studies of
indomethacin and Eudragit(R) E PO by thermal, rheological, and spectroscopic
analysis. J. Pharm. Sci. 101, 2204–2212.
 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Liu, X., Lu, M., Guo, Z., Huang, L., Feng, X., Wu, C., 2012b. Improving the chemical
stability of amorphous solid dispersion with cocrystal technique by hot melt
extrusion. Pharm. Res. 29, 806–817.
Liu, H., Zhu, L., Wang, P., Zhang, X., Gogos, C.G., 2011. Effects of screw configuration
on indomethacin dissolution behavior in Eudragit E PO. Adv. Polym. Technol. 31
(4), 331–342.
Liu, L., Jin, T.Z., Coffin, D.R., Hicks, K.B., 2009. Preparation of antimicrobial mem-
branes: coextrusion of poly(lactic acid) and Nisaplin in the presence of
Plasticizers. J. Agric. Food Chem. 57, 8392–8398.
Lowinger, M., 2011. Process development: scaling a melt extrusion process from
conception to commercialization. Am. Pharm. Rev., March 01.
Lu, J., Shah, S., Jo, S., Repka, M.A.,2011. Solubility enhancement and precipita-
tion inhibition of paclitaxel using hot melt extrusion technology. In: American
Association of Pharmaceutical Scientists Annual Meeting and Exposition. Wash-
ington Convention Center, Washington, DC, USA (abstract ID: W5246).
Lu, J., Shah, S., Repka, M.A.,2012. Solid dispersions of carbamazepine with Lutrol®
F127 using hot melt extrusion. In: 39th CRS Annual Meeting & Exposition. Centre
des Congrès de Québec, Québec City, Canada (abstract ID: 100626).
Ma, D., Djemai, A., Gendron, C.M., Xi, H., Smith, M., Kogan, J., Li, L., 2012. Development
of a HPMC-based controlled release formulation with hot melt extrusion (HME).
Drug Dev. Ind. Pharm, http://dx.doi.org/10.3109/03639045.2012.702350.
Mackin, L., Zanon, R., Park, J.M., Foster, K., Opalenik, H., Demonte, M., 2002. Quantifi-
cation of low levels (<10%) of amorphous content in micronised active batches
using dynamic vapour sorption and isothermal microcalorimetry. Int. J. Pharm.
231, 227–236.
Maclean, J., Medina, C., Daurio, D., Alvarez-Nunez, F., Jona, J., Munson, E., Nagapudi, K.,
2011. Manufacture and performance evaluation of a stable amorphous complex
of an acidic drug molecule and neusilin. J. Pharm. Sci. 100, 3332–3344.
Marsac, P.J., Konno, H., Rumondor, A.C., Taylor, L.S., 2008. Recrystallization of nifedip-
ine and felodipine from amorphous molecular level solid dispersions containing
poly(vinylpyrrolidone) and sorbed water. Pharm. Res. 25, 647–656.
Marsac, P.J., Konno, H., Taylor, L.S., 2006. A comparison of the physical stability of
amorphous felodipine and nifedipine systems. Pharm. Res. 23, 2306–2316.
Marsac, P.J., Rumondor, A.C., Nivens, D.E., Kestur, U.S., Stanciu, L., Taylor, L.S., 2010.
Effect of temperature and moisture on the miscibility of amorphous dispersions
of felodipine and poly(vinyl pyrrolidone). J. Pharm. Sci. 99, 169–185.
Mathot, V.B.F., Goderis, B., Scherrenberg, R.L., van der Vegte, E.W., 2002. High-speed
calorimetry for the study of the kinetics of (de)vitrification, crystallization, and
melting of macromolecules. Macromolecules 35, 3601–3613.
Matsumoto, T., Zografi, G., 1999. Physical properties of solid molecular dispersions of
indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-
acetate) in relation to indomethacin crystallization. Pharm. Res. 16, 1722–1728.
Mccrum, N.G., Buckley, C.P., 1997. Principles of Polymer Engineering. Oxford Uni-
versity Press, Oxford.
McGinity, J.W., Koleng, J.J., 1997. Preparation and evaluation of rapid-release gran-
ules using a novel hot-melt extrusion technique. In: Pharmaceutical Technology
Conference. Pharmaceutical Technology, pp. 153–154.
Mididoddi, P.K., Repka, M.A., 2007. Characterization of hot-melt extruded drug deliv-
ery systems for onychomycosis. Eur. J. Pharm. Biopharm. 66, 95–105.
Miller, D.A., DiNunzio, J.C., Yang, W., McGinity, J.W., Williams 3rd, R.O., 2008.
Targeted intestinal delivery of supersaturated itraconazole for improved oral
absorption. Pharm. Res. 25, 1450–1459.
Miller, D.A., McConville, J.T., Yang, W., Williams 3rd, R.O., McGinity, J.W., 2007. Hot-
melt extrusion for enhanced delivery of drug particles. J. Pharm. Sci. 96, 361–376.
Miyazaki, T., Yoshioka, S., Aso, Y., Kojima, S., 2004. Ability of polyvinylpyrrolidone
and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen.
J. Pharm. Sci. 93, 2710–2717.
Mohammed, N., Majumdar, S., Repka, M.A., Durig, T.,2011. Tablets manufactured via
HME as a processing technique for solubility enhancement: stability assessment
and in vitro release comparison to a marketed fromulation. In: American Associ-
ation of Pharmaceutical Scientists Annual Meeting and Exposition. Washington
Convention Center, Washington, DC, USA (abstract ID: #T3277).
Moran, A., Buckton, G., 2009. Studies of the crystallization of amorphous trehalose
using simultaneous gravimetric vapor sorption/near IR (GVS/NIR) and modu-
lated GVS/NIR. AAPS PharmSciTech 10, 297–302.
Nakamichi, K., Nakano, T., Yasuura, H., Izumi, S., Kawashima, Y., 2002. The role of the
kneading paddle and the effects of screw revolution speed and water content on
the preparation of solid dispersions using a twin-screw extruder. Int. J. Pharm.
241, 203–211.
Newman, A., Engers, D., Bates, S., Ivanisevic, I., Kelly, R.C., Zografi, G., 2008. Charac-
terization of amorphous API:polymer mixtures using X-ray powder diffraction.
J. Pharm. Sci. 97, 4840–4856.
Newman, A., Knipp, G., Zografi, G., 2012. Assessing the performance of amorphous
solid dispersions. J. Pharm. Sci. 101, 1355–1377.
Nishi, T., Wang, T.T., 1975. Melting point depression and kinetic effects of cool-
ing on crystallization in poly(vinylidene fluoride)–poly(methyl methacrylate)
mixtures. Macromolecules 8, 909–915.
Nollenberger, K., Gryczke, A., Meier, C., Dressman, J., Schmidt, M.U., Bruhne, S., 2009.
Pair distribution function X-ray analysis explains dissolution characteristics of
felodipine melt extrusion products. J. Pharm. Sci. 98, 1476–1486.
O’Neill, M.A., Gaisford, S., 2011. Application and use of isothermal calorimetry in
pharmaceutical development. Int. J. Pharm. 417, 83–93.
Onoue, S., Takahashi, H., Kawabata, Y., Seto, Y., Hatanaka, J., Timmermann, B.,
Yamada, S., 2010. Formulation design and photochemical studies on nanocrys-
tal solid dispersion of curcumin with improved oral bioavailability. J. Pharm. Sci.
99, 1871–1881.
251
Ozkan, S., Kalyon, D.M., Yu, X., McKelvey, C.A., Lowinger, M., 2009. Multifunc-
tional protein-encapsulated polycaprolactone scaffolds: fabrication and in vitro
assessment for tissue engineering. Biomaterials 30, 4336–4347.
Perissutti, B., Newton, J.M., Podczeck, F., Rubessa, F., 2002. Preparation of extruded
carbamazepine and PEG 4000 as a potential rapid release dosage form. Eur. J.
Pharm. Biopharm. 53, 125–132.
Prodduturi, S., Manek, R.V., Kolling, W.M., Stodghill, S.P., Repka, M.A., 2004. Water
vapor sorption of hot-melt extruded hydroxypropyl cellulose films: effect on
physico-mechanical properties, release characteristics, and stability. J. Pharm.
Sci. 93, 3047–3056.
Prodduturi, S., Urman, K.L., Otaigbe, J.U., Repka, M.A., 2007. Stabilization of hot-melt
extrusion formulations containing solid solutions using polymer blends. AAPS
PharmSciTech 8 (2), E152–E161 (article 50).
Qi, S., Belton, P., Nollenberger, K., Clayden, N., Reading, M., Craig, D.Q., 2010. Char-
acterisation and prediction of phase separation in hot-melt extruded solid
dispersions: a thermal, microscopic and NMR relaxometry study. Pharm. Res.
27, 1869–1883.
Qi, S., Belton, P., Nollenberger, K., Gryczke, A., Craig, D.Q., 2011. Compositional analy-
sis of low quantities of phase separation in hot-melt-extruded solid dispersions:
a combined atomic force microscopy, photothermal fourier-transform infrared
microspectroscopy, and localised thermal analysis approach. Pharm. Res. 28,
2311–2326.
Qi, S., Craig, D.Q., 2010. Detection of phase separation in hot melt extruded solid
dispersion formulations global vs localized characterization. Am. Pharm. Rev.,
September 01.
Qi, S., Gryczke, A., Belton, P., Craig, D.Q., 2008. Characterisation of solid disper-
sions of paracetamol and EUDRAGIT E prepared by hot-melt extrusion using
thermal, microthermal and spectroscopic analysis. Int. J. Pharm. 354, 158–
167.
Qian, F., Huang, J., Hussain, M.A., 2010. Drug–polymer solubility and miscibility:
stability consideration and practical challenges in amorphous solid dispersion
development. J. Pharm. Sci. 99, 2941–2947.
Ranzani, L.S., Font, J., Galimany, F., Santanach, A., Gomez-Gomar, A.M., Casadevall,
G., Gryczke, A., 2011. Enhanced in vivo absorption of CB-1 antagonist in rats via
solid solutions prepared by hot-melt extrusion. Drug Dev. Ind. Pharm. 37 (6),
694–701.
Rathore, A.S., Bhambure, R., Ghare, V., 2010. Process analytical technology (PAT) for
biopharmaceutical products. Anal. Bioanal. Chem. 398, 137–154.
Rauwendaal, C., 1994. Polymer Extrusion, 3rd ed. Hanser Publisher, Munich.
Rauwendaal, C., 2001. Polymer Extrusion, 3rd ed. Hanser Publisher, Munich.
Read, E.K., Park, J.T., Shah, R.B., Riley, B.S., Brorson, K.A., Rathore, A.S., 2010. Process
analytical technology (PAT) for biopharmaceutical products: Part I. concepts and
applications. Biotechnol. Bioeng. 105, 276–284.
Reitz, C., Strachan, C., Kleinebudde, P., 2008. Solid lipid extrudates as sustained-
release matrices: the effect of surface structure on drug release properties. Eur.
J. Pharm. Sci. 35, 335–343.
Repka, M.A., Battu, S.K., Upadhye, S.B., Thumma, S., Crowley, M.M., Zhang, F., Martin,
C., McGinity, J.W., 2007. Pharmaceutical applications of hot-melt extrusion: part
II. Drug Dev. Ind. Pharm. 33, 1043–1057.
Repka, M.A., Gerding, T.G., Repka, S.L., McGinity, J.W., 1999. Influence of plasticiz-
ers and drugs on the physical–mechanical properties of hydroxypropylcellulose
films prepared by hot melt extrusion. Drug Dev. Ind. Pharm. 25, 625–633.
Repka, M.A., Majumdar, S., Kumar Battu, S., Srirangam, R., Upadhye, S.B., 2008. Appli-
cations of hot-melt extrusion for drug delivery. Expert Opin. Drug Deliv. 5,
1357–1376.
Repka, M.A., McGinity, J.W., Zhang, F., 2002. Hot-Melt Extrusion Technology, 2nd ed.
Marcel Dekker Inc., New York.
Repka, M.A., Shah, S., Lu, J., Maddineni, S., Morott, J., Patwardhan, K., Mohammed,
N.N., 2012. Melt extrusion: process to product. Expert Opin. Drug Deliv. 9,
105–125.
Roblegg, E., Jager, E., Hodzic, A., Koscher, G., Mohr, S., Zimmer, A., Khinast, J., 2011.
Development of sustained-release lipophilic calcium stearate pellets via hot
melt extrusion. Eur. J. Pharm. Biopharm. 79, 635–645.
Rodrigues, L.O., Alves, T.P., Cardoso, J.P., Menezes, J.C., 2006. Improving drug manu-
facturing with process analytical technology. IDrugs 9, 44–48.
Rumondor, A., Ivanisevic, I., Bates, S., Alonzo, D., Taylor, L., 2009a. Evaluation of
drug–polymer miscibility in amorphous solid dispersion systems. Pharm. Res.
26, 2523–2534.
Rumondor, A.C., Marsac, P.J., Stanford, L.A., Taylor, L.S., 2009b. Phase behavior of
poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence
of moisture. Mol. Pharm. 6, 1492–1505.
Rumondor, A.C., Taylor, L.S., 2010. Application of partial least-squares (PLS) model-
ing in quantifying drug crystallinity in amorphous solid dispersions. Int. J. Pharm.
398, 155–160.
Rumondor, A.C., Wikstrom, H., Van Eerdenbrugh, B., Taylor, L.S., 2011.
Understanding the tendency of amorphous solid dispersions to undergo
amorphous–amorphous phase separation in the presence of absorbed
moisture. AAPS PharmSciTech 12, 1209–1219.
Saerens, L., Dierickx, L., Lenain, B., Vervaet, C., Remon, J.P., De Beer, T., 2011. Raman
spectroscopy for the in-line polymer–drug quantification and solid state char-
acterization during a pharmaceutical hot-melt extrusion process. Eur. J. Pharm.
Biopharm. 77, 158–163.
Saerens, L., Dierickx, L., Quinten, T., Adriaensens, P., Carleer, R., Vervaet, C., Remon,
J.P., De Beer, T., 2012. In-line NIR spectroscopy for the understanding of
polymer–drug interaction during pharmaceutical hot-melt extrusion. Eur. J.
Pharm. Biopharm. 81 (1), 230–237.
252 S. Shah et al. / International Journal of Pharmaceutics 453 (2013) 233–252
Sakurai, A., Sakai, T., Sako, K., Maitani, Y., 2012. Polymer combination increased
both physical stability and oral absorption of solid dispersions containing a low
glass transition temperature drug: physicochemical characterization and in vivo
study. Chem. Pharm. Bull. (Tokyo) 60, 459–464.
Saleki-Gerhardt, A., Ahlneck, C., Zografi, G., 1994. Assessment of disorder in crys-
talline solids. Int. J. Pharm. 101, 237–247.
Sathigari, S.K., Radhakrishnan, V.K., Davis, V.A., Parsons, D.L., Babu, R.J., 2012.
Amorphous-state characterization of efavirenz-polymer hot-melt extrusion
systems for dissolution enhancement. J. Pharm. Sci. 101 (9), 3456–3464.
Saunders, M., Podluii, K., Shergill, S., Buckton, G., Royall, P., 2004. The potential of high
speed DSC (hyper-DSC) for the detection and quantification of small amounts
of amorphous content in predominantly crystalline samples. Int. J. Pharm. 274,
35–40.
Schilling, S.U., Bruce, C.D., Shah, N.H., Malick, A.W., McGinity, J.W., 2008. Citric acid
monohydrate as a release-modifying agent in melt extruded matrix tablets. Int.
J. Pharm. 361, 158–168.
Schilling, S.U., Lirola, H.L., Shah, N.H., Waseem Malick, A., McGinity, J.W., 2010. Influ-
ence of plasticizer type and level on the properties of Eudragit S100 matrix
pellets prepared by hot-melt extrusion. J. Microencapsul. 27, 521–532.
Schilling, S.U., Shah, N.H., Malick, A.W., Infeld, M.H., McGinity, J.W., 2007. Citric
acid as a solid-state plasticizer for Eudragit RS PO. J. Pharm. Pharmacol. 59,
1493–1500.
Scott, B., Wilcock, A., 2006. Process analytical technology in the pharmaceutical
industry: a toolkit for continuous improvement. PDA J. Pharm. Sci. Technol. 60,
17–53.
Serajuddin, A.T., 1999. Solid dispersion of poorly water-soluble drugs: early
promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88,
1058–1066.
Shah, N., Choi, S.H.D.S., Kalb, O., Page, S., Wyttenbach, N., 2012. Structured develop-
ment approach for amorphous systems. In: Williams III, R.O., Watts, A.B., Miller,
D.A. (Eds.), Formulating Poorly Water Soluble Drugs. Springer, New York, NY,
pp. 267–310.
Sherry, R., 2007. Reckitt Benckiser Healthcare (UK) Limited Assignee. Granules com-
prising paracetamol, a NSAID and a sugar alcohol made by melt extrusion patent.
Shibata, Y., Fujii, M., Sugamura, Y., Yoshikawa, R., Fujimoto, S., Nakanishi, S., Moto-
sugi, Y., Koizumi, N., Yamada, M., Ouchi, K., Watanabe, Y., 2009. The preparation
of a solid dispersion powder of indomethacin with crospovidone using a twin-
screw extruder or kneader. Int. J. Pharm. 365, 53–60.
Six, K., Murphy, J., Weuts, I., Craig, D.Q., Verreck, G., Peeters, J., Brewster, M., Van
den Mooter, G., 2003. Identification of phase separation in solid dispersions of
itraconazole and Eudragit E100 using microthermal analysis. Pharm. Res. 20,
135–138.
Smith, A.J., Kavuru, P., Wojtas, L., Zaworotko, M.J., Shytle, R.D., 2011. Cocrystals
of quercetin with improved solubility and oral bioavailability. Mol. Pharm. 8,
1867–1876.
Steiner, R., 2003. Extruder design. In: Ghebre-Sellassie, I.M.C. (Ed.), Pharmaceutical
Extrusion Technology. Marcel Dekker, New York, pp. 20–38.
Sun, Y., Rui, Y., Wenliang, Z., Tang, X., 2008. Nimodipine semi-solid capsules con-
taining solid dispersion for improving dissolution. Int. J. Pharm. 359, 144–149.
Taylor, L.S., Zografi, G., 1997. Spectroscopic characterization of interactions between
PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 14,
1691–1698.
Thiele, W., 2003. Twin-screw extrusion and screw design. In: Ghebre-Sellassie,
I.M.C. (Ed.), Pharmaceutical Extrusion Technology. Marcel Dekker, New York,
pp. 69–98.
Tho, I., Liepold, B., Rosenberg, J., Maegerlein, M., Brandl, M., Fricker, G., 2010. For-
mation of nano/micro-dispersions with improved dissolution properties upon
dispersion of ritonavir melt extrudate in aqueous media. Eur. J. Pharm. Sci. 40,
25–32.
Thommes, M., Baert, L., Rosier, J., 2010. 800 mg Darunavir tablets prepared by hot
melt extrusion. Pharm. Dev. Technol. 16 (6), 645–650.
Thommes, M., Ely, D.R., Carvajal, M.T., Pinal, R., 2011. Improvement of the dissolution
rate of poorly soluble drugs by solid crystal suspensions. Mol. Pharm. 8, 727–735.
Tumuluri, V.S., Kemper, M.S., Lewis, I.R., Prodduturi, S., Majumdar, S., Avery, B.A.,
Repka, M.A., 2008. Off-line and on-line measurements of drug-loaded hot-melt
extruded films using Raman spectroscopy. Int. J. Pharm. 357, 77–84.
Upadhye, S.B., Kulkarni, S.J., Majumdar, S., Avery, M.A., Gul, W., ElSohly, M.A.,
Repka, M.A., 2010. Preparation and characterization of inclusion complexes of
a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified
beta-cyclodextrins. AAPS PharmSciTech 11, 509–517.
Uzun, I.N., Sipahigil, O., Dincer, S., 2011. Coprecipitation of Cefuroxime Axetil-PVP
composite microparticles by batch supercritical antisolvent process. The Journal
of Supercritical Fluids 55, 1059–1069.
Van den Mooter, G., 2012. The use of amorphous solid dispersions: a formulation
strategy to overcome poor solubility and dissolution rate. Drug Discov. Today:
Technol. 9, e79–e85.
Van den Mooter, G., Wuyts, M., Blaton, N., Busson, R., Grobet, P., Augustijns, P., Kinget,
R., 2001. Physical stabilisation of amorphous ketoconazole in solid dispersions
with polyvinylpyrrolidone K25. Eur. J. Pharm. Sci. 12, 261–269.
Van Eerdenbrugh, B., Lo, M., Kjoller, K., Marcott, C., Taylor, L.S., 2012a. Nanoscale
mid-infrared evaluation of the miscibility behavior of blends of dextran or mal-
todextrin with poly(vinylpyrrolidone). Mol. Pharm. 9, 1459–1469.
Van Eerdenbrugh, B., Lo, M., Kjoller, K., Marcott, C., Taylor, L.S., 2012b. Nanoscale
mid-infrared imaging of phase separation in a drug–polymer blend. J. Pharm.
Sci. 101, 2066–2073.
Vasconcelos, T., Sarmento, B., Costa, P., 2007. Solid dispersions as strategy to
improve oral bioavailability of poor water soluble drugs. Drug Discov. Today
12, 1068–1075.
Verhoeven, E., De Beer, T.R., Van den Mooter, G., Remon, J.P., Vervaet, C., 2008. Influ-
ence of formulation and process parameters on the release characteristics of
ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion.
Eur. J. Pharm. Biopharm. 69, 312–319.
Verhoeven, E., De Beer, T.R.M., Schacht, E., Van den Mooter, G., Remon, J.P., Vervaet,
C., 2009. Influence of polyethylene glycol/polyethylene oxide on the release
characteristics of sustained-release ethylcellulose mini-matrices produced by
hot-melt extrusion: in vitro and in vivo evaluations. Eur. J. Pharm. Biopharm.
72, 463–470.
Verreck, G., Six, K., Van den Mooter, G., Baert, L., Peeters, J., Brewster, M.E., 2003.
Characterization of solid dispersions of itraconazole and hydroxypropylmethyl-
cellulose prepared by melt extrusion—part I. Int. J. Pharm. 251, 165–174.
Vyazovkin, S., Dranca, I., 2007. Effect of physical aging on nucleation of amorphous
indomethacin. J. Phys. Chem. B 111, 7283–7287.
Yang, M., Wang, P., Gogos, C., 2012. Prediction of acetaminophen’s solubility in
poly(ethylene oxide) at room temperature using the Flory-Huggins theory. Drug
Dev. Ind. Pharm., http://dx.doi.org/10.3109/03639045.2012.659188.
Yang, M., Wang, P., Suwardie, H., Gogos, C., 2011. Determination of acetaminophen’s
solubility in poly(ethylene oxide) by rheological, thermal and microscopic meth-
ods. Int. J. Pharm. 403, 83–89.
Yano, H., Kleinebudde, P., 2010. Improvement of dissolution behavior for poorly
water-soluble drug by application of cyclodextrin in extrusion process:
comparison between melt extrusion and wet extrusion. AAPS PharmSciTech 11,
885–893.
Yoo, S.U., Krill, S.L., Wang, Z., Telang, C., 2009. Miscibility/stability considerations in
binary solid dispersion systems composed of functional excipients towards the
design of multi-component amorphous systems. J. Pharm. Sci. 98, 4711–4723.
Yoshioka, M., Hancock, B.C., Zografi, G., 1995. Inhibition of indomethacin crystalliza-
tion in poly(vinylpyrrolidone) coprecipitates. J. Pharm. Sci. 84, 983–986.
Yu, L.X., Lionberger, R.A., Raw, A.S., D’Costa, R., Wu, H., Hussain, A.S., 2004. Appli-
cations of process analytical technology to crystallization processes. Adv. Drug
Deliv. Rev. 56, 349–369.
Zhao, Y., Inbar, P., Chokshi, H.P., Malick, A.W., Choi, D.S., 2011. Prediction of the ther-
mal phase diagram of amorphous solid dispersions by Flory–Huggins theory.
J. Pharm. Sci. 100, 3196–3207.
Zheng, X., Yang, R., Tang, X., Zheng, L., 2007. Part I: characterization of solid disper-
sions of nimodipine prepared by hot-melt extrusion. Drug Dev. Ind. Pharm. 33,
791–802.