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Int J Pharm. Author manuscript; available in PMC 2021 December 21.
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Published in final edited form as:

Int J Pharm. 2020 August 30; 586: 119560. doi:10.1016/j.ijpharm.2020.119560.
Amorphous solid dispersions: An update for preparation,

characterization, mechanism on bioavailability, stability,
regulatory considerations and marketed products
Palpandi Pandia,1, Raviteja Bulusub,1, Nagavendra Komminenic,1, Wahid Khand,*, Mandip
Singhc,*
aDepartmentof Pharmacy, Employee State Insurance Corporation Medical College and Hospital,
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Chennai 600078, India

bDepartment of Pharmaceutics, Jawaharlal Nehru Technological University, Kakinada 533003,
India
cCollege of Pharmacy, Florida Agriculture and Mechanical University, FL 32307, USA
dNatco Research Centre, NATCO Pharma Limited, Hyderabad 500018, India
Abstract
Amorphous solid dispersions (ASDs) are being employed frequently to improve bioavailability
of poorly soluble molecules by enhancing the rate and extant of dissolution in drug product
development process. These systems comprise of an amorphous active pharmaceutical ingredient
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stabilized by a polymer matrix to provide enhanced stability. This review discussed the
methodologies of preparation and characterization of ASDs with an emphasis on understanding
and predicting stability. Rational selection of polymers, preparation techniques with its advantages
and disadvantages and characterization of polymeric amorphous solid dispersions have discussed.
Stability aspects have been described as per ICH guidelines which intend to depend on selection
of polymers and preparation methods of ASD. The mechanism involved on improvement of
bioavailability also considered. Regulatory importance of ASD and current evolving details of
QBD approach were reviewed. Amorphous products and particularly ASDs are currently most
emerging area in the pharmaceutical field. This strategic approach presents huge impact and
advantageous features concerning the overall improvement of drug product performance in clinical
settings which ultimately lead to drug product approval by leading regulatory agencies into the
market.
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Keywords
Amorphous products; Solubility; Permeability; Stability; Regulatory
*
Corresponding authors at: Department of Novel Drug Delivery system (NDDS), Natco Reseach Centre, NATCO Pharma Limited,
Sanath Nagar, Hyderabad 500018, India (W. Khan), Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M
University, Tallahassee, FL 32307, USA (M. Singh). mail4wahid@gmail.com (W. Khan), mandip.sachdeva@famu.edu (M. Singh).
1Equal Contributors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Pandi et al. Page 2
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1. Introduction
Last two decades the new chemical entities in pharmaceutical research (NCE) are
poorly water soluble and for those molecules/compounds solution formulations are often
unachievable. It was reported that the Food and Drug Administration (FDA) has been
approved 19 commercial ASD products in the period from 2007 to 2017 (DeBoyace,
2019; Jermain et al., 2018). When poor water solubility is the main hindrance due to the
lipophilicity of a compound, formulations such as lipid-based emulsions, self-emulsifying
(nano or micro) drug delivery systems (SNEDDS, SMEDDS, SEDDS), liposomes, and so
on may be viable options, but their utility is limited as the drug content is typically low
in these types of systems (Hamner, 2019). Biopharmaceutical Classification System (BCS)
involves mathematical analysis to experimentally determine solubility and permeability
of drugs (Saxena and Jain, 2019). Amorphous solid dispersions (ASDs) are being used
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recurrently for poorly soluble pharmaceutical compounds. In an ASD, the solubility of

the drug substance is improved by disarranging its crystalline lattice to produce a higher
energy state of amorphous form (Duarte et al., 2015; Elgindy et al., 2011). Polymers
also play a key role to improve the solubility and bioavailability of amorphous API by
drug polymer interaction. The polymer could stabilize the ASD and prevent the drug from
crystallization and to provide improved physical stability under a variety of accelerated
stability conditions, such as elevated temperature and relative humidity. Compared with
other reported solubilization approaches, an ASD can prefer for low-solubility active
pharmaceutical ingredients (APIs). ASD maintains its supersaturation in the gastrointestinal
(GI) tract which is the reason for the improvement of bioavailability (Newman et al.,
2015). When supersaturation is controlled, the absorption of a compound can be increased
to be more than that of a saturated solution condition. Furthermore, among different
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crystalline forms solubility can be eliminated as they are converted to the amorphous form
(LaFountaine et al., 2016). Many toxicologist and well established animal models were
developed and they accepted as their polymer carriers are derived from GRAS (generally
regarded as safe) excipients (Ayad et al., 2013). Usually used excipients for forming
ASDs are cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxy
ethyl cellulose, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate
(CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC),
methyl cellulose, chitosan, carboxymethyl cellulose, ethyl cellulose, carboxymethyl ethyl
cellulose, cyclodextrin and derivatives, lactose, poloxamers, polyvinylpyrrolidone (PVP),
polymethacrylates (Eudragit E, L, S, FS), polyvinylpyrrolidone-vinyl acetate copolymer
(PVP/VA 64), polyvinyl acetate phthalate (PVAP), and polyethylene glycols (PEG)
derivatives. These polymers are biologically inactive and less absorbed in GIT (Sihorkar and
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Dürig, 2020). ASD are generally prepared using methods based on solvent evaporation (SE)
or melt cooling. The processing technologies include spray drying (SD), hot-melt extrusion
(HME), KinetiSolR dispersing (KSD), drum drying, freeze-drying (FD), rotary evaporation
(RE), spray congealing, co-precipitation (CP), co-grinding, spin-coated film (SCF),
centrifuge vacuum drying (CVD), supercritical fluid technology, electrostatic spinning, and
microwave technology (Kumar, 2020). HME is most preferred option in pharmaceutical
development because of the various advantages like favorable good powder properties, no

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organic solvents in the processing, small footprint of the equipment, ease of increasing
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batch size, feasibility and scalability from, pilot to industrial setting, and suitability of
batch processing. However, requires more API hence the application of HME in discovery
research is limited for screening (Bandari et al., 2020; Hwang et al., 2020). Even larger
amounts of API are required for KSD and drum drying. Rota evaporation is a good choice
for discovery, but it has much scale up issues for the development. Supercritical fluid
technology, electrostatic spinning, and microwave technology are still under development
and have yet to be proven in pharmaceutical R&D (ROTA-EVAPORATION, 2015). Freeze
drying is used for water soluble API and it is not suitable for polymer carriers can only
be dissolved in organic solvents. In addition, the FD process cost effective than SD,
which renders FD a cost-ineffective choice for production. Nevertheless, SD is usually the
technique of choice to prepare ASD in discovery stage when drug substance is only available
in limited quantities (Ardeshana et al., 2020). In SD technology, wide ranges of polymers
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can be screened and same. The objective of this review is to comprehend current ASDs,
utilization, and limits of applications. This review will discuss methods of preparation and
characterization of ASDs with an emphasis on understanding and predicting stability.
2. Amorphous solid dispersion

2.1. Amorphous state (solid state details)
Amorphous pharmaceutical materials are thermodynamically metastable state and readily
may convert into the more stable crystalline form. Quasi-equilibrium thermodynamic
view of the amorphous form has higher solubility than crystalline form because it has
a significantly higher free energy than the crystalline form (Lapuk et al., 2019a). It is
illustrated that, amorphous materials are glassy nature and super cooled liquid and it can
be achieved by rapid cooling. The molecular mobility is gradually reduced as the material
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is cooled, and the viscosity of the material increases simultaneously. This is called as
glass transition temperature and state of the material called as glassy (Shekunov, 2019).
However, glassy materials are metastable in nature and relative to both the equilibrium
supercooled liquid and the crystalline forms of the material, and it was related to long
term physical stability to be performed before the manufacture of pharmaceutical products
(Hilfiker and von Raumer, 2019). The glass transition is associated with changes happened
in various thermodynamic properties such as enthalpy, entropy and process volume. Also it
characterized as second order thermodynamic transition (Newman and Zografi, 2020). Many
literatures are available for such studies which have deals with amorphous drug delivery
systems.
2.2. Amorphous solid dispersion

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Bioavailability of drug can be ultimately improved by amorphous solid dispersion when

drug available in amorphous form. The selection of suitable polymer carrier helps to
increase rate of dissolution, enhancement of solubility of the drug and to improve the
solid-state physical stability as well. A polymer carrier involved in the process of conversion
of crystalline drug to its amorphous form and also it stabilizes the ASD by reducing
the molecular mobility and extending its glass transition temperature (Tg). The stability
of an ASD is certainly the result of disrupting intermolecular interactions in the drug’s

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crystal lattice and forming drug–polymer interactions. The crystal lattice nature of the drug
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disrupting the intermolecular interactions by polymers and it affects the stability of ASD.
The thermodynamic and kinetic forces are responsible for enhancement of bioavailability of
ASD (Vo et al., 2013).
The steric hindrance can create the larger surface area and it will act on crystallization
inhibition and it also prevents the nucleation on crystal growth. The Noyes-Whitney
equation is suitable to correlate the surface area and dissolution. As surface increases
dissolution rate also simultaneously increases (Gibaldi and Feldman, 1967). The initial
step of dissolution is wetting of the molecule and it can be facilitated by water soluble
polymers. Even fail to achieve complete dissolution release profile, generated supersaturated
solution and improved GI transit time enhances the absorption kinetics of the molecule.
ASD can also improve the permeation rate by the spontaneously formed microparticles- or
nanoparticles or micelles in the GI tract.
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3. BCS classification
Solubility and permeability play crucial role in the per-oral drug absorption. Amidon et al.
described based on dimensionless frames. BCS classification system is extensively used by
the pharmaceutical industries across drug discovery and development (Charalabidis et al.,
2019). The United States Food and drug administration, European medicine agency (EMEA)
and World Health organization (WHO) have been accepted this proposal and using for
Bioavailability bioequivalence study approval. The ICH also widely accepted BCS system
for in-vitro dissolution in manufacturing quality control. Besides solubility and permeability
of drug, three fundamental dimensionless numbers say absorption number, dissolution
number and dose number also plays an important role (Bransford et al., 2019). Various
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limitations of BCS system were observed and discussed below. The BCS classification
system and formulation approaches for respective class were mentioned in Fig. 1.
4. Selection of polymers in ASD

Owing to limited drug availability at an early stage drug development, selection of
suitable polymers are necessary to characterize and correlate with drugs physico-chemical
properties including melting enthalpy, Tg, molecular weight, solvent miscibility and
solubility, structural flexibility and viscosity of drug and polymer above and below its
Tg. Though few compounds have good glass forming ability low crystallization tendency,
its amorphous forms are however thermodynamically unstable. As amorphous forms are
thermodynamically unstable, it was identified as good glass formers with low crystallization
tendencies. Amorphous solid dispersion is incorporation of amorphous drug into the selected
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polymers which alter the kinetics of conversion of crystalline and super saturation of the
molecule (Bhargavi et al., 2018; Trivino et al., 2019). The selection of suitable polymer
determines the alteration of physicochemical properties of drugs. The selection of ideal
polymer plays major roles in the dispersion are (i) it should have the ability of maintaining
the drug in amorphous form not only during manufacturing also in storage and shipment
as well. (ii) It should have readily soluble in GI conditions and need to maintain the
supersaturated solution state which is necessary for drug absorption. (iii) it also should have

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an ability to improve the bioavailability by enhancing the permeation of drug through GI

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membranes (He and Ho, 2015).
5. Methodologies for ASD

Various preparation techniques were reported and captured in Fig. 2. Those techniques
are melt fusion technique like hot melt extrusion, SCF cryogenic techniques, solvent
evaporation technique including spray drying and solvent evaporation by rota evaporator,
cyclodextrin-based inclusion complex techniques (co-evaporation, kneading, lyophilization/
freeze-Drying technique, microwave irradiation method), electrostatic spinning, electrostatic
blowing, electrospraying film casting. These techniques designed based on principles of
molecular solubilizing mechanism such as micellar solubilization, complexation, increased
porosity, or decreased particle size, and it should be deviated from polymer-based ASD
(He and Ho, 2015). The different methods for preparing amorphous solid dispersion are
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discussed in this review.
List and description of some recent studies employed on ASD has been captured in Table 1.
6. Characterization of ASD
The sound knowledge about recrystallization of ASD is required to understand
the characterization and stability. Quality by Design principles demands a thorough
understanding of the processes taking place at a molecular level and particle level. No single
characterization technique can give the full picture of ASD and among those articles, few of
them selected and highlighted in Table 2.
7. Mechanism of ASD on increasing bioavailability

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In this review we are extending to discuss the drug uptake mechanism from ASD which
was investigated various researchers. When ASD is contact with aqueous medium, solution
state spontaneous dissolution takes place. Furthermore, API becomes micelles, crystal or
amorphous suspensions and drug rich particles. Few references discussed that formation of
colloidal system of ASD may induces the intestinal uptake of dissolved API (Amidon et al.,
1995). Absorption of API is multi step process and those are (i) Dissolution of ASD into the
dissolution media, (ii) Drug uptake from dissolved API, (iii) Equilibrium of API in dissolved
API solution. Theoretically, solution state classified as crystalline stability which is API
solution in maximum concentration and amorphous solubility which is API supersaturated
solution with maximum concentration (Arca et al., 2017). Crystalline solubility (or could
be pronounced as solubility) is a result of the thermodynamic equilibrium between an
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excess of crystalline solid and dissolved API in a dissolution medium, whereby strictly seen
the crystalline structure should be the most stable polymorph. An amorphous solid also
following the same concept in its dissolution, except that this equilibrium is metastable, i.e.
is not a thermodynamic equilibrium, and it exists between the amorphous state of the drug
and its solution form in the absence of any crystalline material. If a supersaturated drug
solution exceeds the amorphous solubility, this amorphous phase will form spontaneously.
Amorphous liquid phase separation is defined as drug rich particles are metastable in nature

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and crystallization occurs spontaneously. Amorphous compounds have desired properties of

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higher apparent solubility than their crystalline state owing to their higher energetic state
and the disordered structure that does not require the crystal lattice to be broken while
dissolution. In contrast to the crystalline form of a drug, the amorphous form is in a state
of higher energy. This is because amorphous state holds excess thermodynamic properties
such as enthalpy, entropy and Gibbs free energy. The continuous change in free energy
acts as driving factor for recrystallization. The difference in Gibbs free energy between the
amorphous and the crystalline states can be calculated using enthalpic and entropic values
for the amorphous and crystalline state as shown below equation.
Gconf = Hconf (T ) + Sconf (T )
The term “configurational” denotes the difference between the amorphous and the
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crystalline state and the parameters Hconf and Sconf may be calculated from their
relationship with the heat capacity. The higher the configurational values are the greater
are the differences between the crystalline and the amorphous states (Graeser et al., 2010).
The formation of dissolved ASD is crucial step for the improvement of dissolution profile of
drug and it is directly linked with bioavailability. Craig and Simonelli established the carrier
based and controlled drug release of API of ASD polymer mixture. They have proposed two
concepts and those are followed. If the polymer is does not dissolved in dissolution medium,
it forms a viscous layer, and this will be limiting the drug release from carrier. And the same
way, the polymer is completely dissolved in dissolution medium, it is less chance to form the
viscous layer and predominantly dissolution is drug controlled (Craig, 2002; Simonelli et al.,
1969). There is evidence in the published literature, mainly-three mechanisms are involved
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in dissolution of ASD (Schittny et al., 2020).
7.1. Carrier controlled release

Dissolution media entrapped into the polymer matrix and induces the formation of viscous
gel layer, which the drug molecule can diffuse to the media. This is usually slow process
and concentration of drug is controlled by API in ASD and volume of dissolution media
(Dahlberg et al., 2010; Indulkar et al., 2017; Punčochová et al., 2015).
7.2. Dissolution controlled release

Simultaneously API reaches the super saturation level, as the API and polymer released in
the medium and this fastens the dissolution process. The supersaturation concentration is
controlled by total drug in ASD and volume of dissolution media.
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7.3. Drug controlled release

The polymer and drug dissolves in dissolution media and but amorphous API of ASD
dissolves in controlled rate. But in this mechanism, there is a chance drug to get
crystallization during dissolution and this may happen if amorphous form of drug is stable
enough. Above discussed mechanisms were depicted in Fig. 3.

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8. Stability of amorphous solid dispersion

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Amorphous solid has short order arrangement of molecules in comparison with crystalline
solids which is arranged in three-dimensional array. Amorphous solids have ideal
pharmaceutical properties of greater solubility and higher kinetic solubility when compared
with its crystal form. In in-vivo a well-developed amorphous system can exist in super-
saturated form, and thus enhancing the exposure of the drug. Amidst of all these assets
of ASD the major liability is their poor physical and chemical stability which often rise
challenges in the development of commercialization of the product (Miller et al., 2012;
Tran et al., 2011). The major causes of the instability of the product are due to 1)
Scarce of promising technologies to prognosis the stability of formulation, 2) depletion
in understanding physiochemical properties of API, additives and polymers, 3) dearth
of prejudice on technologies to setup for manufacturing. To curtail imperils of physical
instability these factors should be considered.
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There are many approaches were available to discuss the mechanistic insights and instability
of ASD which was prepared by various techniques. The traditional approach for the
prediction of stability is predicting stability under stress conditions as per ICH guidelines.
Typically long term stability will give a clear picture of ASD formulation with respect
to solid-state properties as well as physical and chemical integrity (Six et al., 2004). As
per ICH Q1 guidelines common set of stress conditions would generally include 2–8 °C
refrigerated, 25 °C/60% RH, 30 °C/65% RH, 30 °C/75% RH, 40 °C/75% RH with time
points ranging from one day up to six months or two years. At every time point under each
stress condition, the sample is analyzed using XRPD, DSC, and/or FTIR as depicted above.
In the late-phase drug development, long-term stability is carried out for years to confirm
the shelf life by either PXRD or DSC. In this case, the objective is not to predict but to
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estimate real-time stability (Committee, 2003)). In addition to the stability assessment of

ASD with the goal for drug product development, the ASD formulation also needs to sustain
supersaturation during the in vivo dissolution testing to achieve the solubility improvement
and to optimize drug absorption. In case of preclinical animal studies, suspension stability
may also be important. The ASD stability is conducted to support pharmacokinetic and/or
toxicology studies. The preferred suspension vehicle is the one in which the API would
remain amorphous for up to 4–6 h at room temperature (Nagapudi and Jona, 2008; Newman
et al., 2015).
8.1. Factors affecting stability

The spontaneous conversion of ASD back into more stable crystalline form can be observed
in meta-stable sate of ASD. The specific interactions between the drug and the polymers
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can lead to the reduction of molecular mobility and molecular coupling which acts as
appended causes for the conversion of amorphous to crystalline form. The factors which
plays prominent role on thermodynamic (responsible for nucleation and crystal growth) and
kinetic (molecular mobility) aspects are processing and storage conditions, parameters such
as temperature and relative humidity (RH) (Korhonen et al., 2008; Wegiel et al., 2013).

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8.2. Thermodynamic aspect

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The solid-state changes will be observed on molecular level when ASD is considered as a
glassy solution of poor soluble drug in hydrophilic polymer having high glass transition. As
thermodynamic driving force is responsible for the crystallization is inversely proportional
to the rate of temperature decreasing and kinetic aspect. This literally means, the boost in
the thermodynamic force with increased rate of supercooling then, there is increase in the
kinetic barrier to crystallization and decrease in molecular mobility (Liu et al., 2020).
A mass of crystalline material is attained by crystal growth after the formation of stable
nucleus through the thermo dynamic driving force of nucleation (Moseson et al., 2020). The
crystal growth diffuses from bulk solution into the interface, which often described by the
equation:
k
u= [1 − exp(ΔG ∕ RT )]
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8.3. Kinetic Aspect: Molecular mobility

The API re-crystallization in solid dispersion can be prevented extensively by kinetic
stabilization of the product. The molecular mobility has a great impact in stabilization which
holds the rotational and transitional movements of the molecule and allows the molecule to
diffuse surface integration (Kapourani et al., 2020; Monschke et al., 2020).
8.4. Effect of temperature on molecular mobility

Temperature has its own stance on the stability of ASD as crystallization is a function of
temperature. The rapid phase separation and crystallization of ASD takes place when there
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is a transition of glass phase to the liquid phase at elevated temperature above Tg (Lapuk
et al., 2019b). Usually, as per the Tg – 50 °C rule, the ASD are recommended to store
at least at a temperature 50 °C less than its Tg. But it is not applicable for ASD when
crystallization is due to α-relaxation. On the flipside there is another possibility to store
the ASD at a temperature where molecular mobility can be ceased entirely is known as
Kauzmann temperature (Tk) (Blaabjerg et al., 2019; Martinez-Garcia et al., 2014).
8.5. Moisture effect on mobility

The ASD stability is greatly influenced by the presence of moisture in the interactions
between the moist and API or the polymer. Those interactions are of two types: absorption
and adsorption of water molecules at bulk or surface levels. As amorphous forms have
higher kinetic solubility than crystalline forms so it absorbs more water when compared
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to crystalline form (Rumondor et al., 2011). Water in the ASD exhibit the plasticizing
effect which lowers the transitional temperature of the ASD and further increases the rate
of crystallization. Plasticizers affect the various parameters in the system by decreasing
the strength, viscosity transitional temperature and increase in molecular mobility which
eventually increases physical and chemical instability (Li et al., 2020).
The polymers also elicit the plasticizing effect when comes in contact with water or moisture
by forming the hydrogen bond between the water, polymer and API and affects the mobility

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of the dispersed API. These can be traced by employing Fourier Transform(FT), near
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infrared techniques, and differential scanning calorimetry (DSC) (Chavan et al., 2017).
9. Regulatory considerations in development of ASD

Amorphous solid dispersion (ASD) provides a scope to improve the bioavailability and
therapeutic efficiency by enhancing the physicochemical properties like solubility of poorly
aqueous soluble drugs. On the other side, manufacturing cost is very less compare to
the other approaches such as such as cosolvent or self-emulsifying drug delivery system
(SEDDS) and an unacceptable level of surfactants and/or solvents, which will not be
acceptable to regulatory authorities (Ivanisevic, 2010). This is a major challenge for the
pharmaceutical companies to maintain the drug in the amorphous solid form in the solid
dispersion with respective to meet the quality specifications parameters and to ensure
expected in vivo performance. The major challenge is unfortunately final dosage forms
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undergoes devitrification especially which the compound has low therapeutic dose such
as tacrolimus 0.4 mg (Janssens and Van den Mooter, 2009). Because of product ages
during storage period, it fails to maintain the regulatory specifications such as dissolution,
crystallization tendency and percentage purity of various regulatory bodies. Additionally,
low-dose drugs also have manufacturing issues like blending and content uniformity. In the
past experience, various ASD products were recalled by FDA due to safety and efficacy
issues (Guo et al., 2013; Sihorkar and Dürig, 2020). Quality by design (QbD) is a new
drug product development platform where quality is a matter of final product rather than
confirmed by quality control analytical tests. In QbD critical quality attributes (CQA)
is used to understand, control and monitor the critical manufacturing steps by utilizing
new technologies and mathematical tools (multivariate analysis). A generic product is the
therapeutic equivalent or copy-cat version of the original drug product, reference listed
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drug (RLD) approved by the FDA. Generic drug manufacturers showing interest to prove
their product is pharmaceutically equivalent and bioequivalent, and hence therapeutically
equivalent to the RLD (L Chaves et al., 2014). The current good manufacturing practices
(cGMP) followed for every drug product and those should also be labelled appropriately
and manufactured with fulfilment of compliance. Since (New drug application) NDA has
already set up the safety and efficacy of the drug, the Abbreviated New Drug Application
(ANDA) sponsor need not to repeat safety and efficacy studies. The data requirement for
filing NDA and ANDA include chemistry, manufacturing, controls, testing, and labelling.
This is the responsibility of the ANDA sponsors to show that their product meets the same
quality standard as that of RLD (FDA, 2007; Food; Food and Administration, 2013).
9.1. Quality by design

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The traditional approach of pharmaceutical development may be called quality by testing

(QbT) this approach is based on the assumption that tighter specific parameters will be
able to detect changes in the formulation and process parameters among batches. Quality
is a main concern for regulatory authorities and it is necessary to develop the stringent
guidelines to ensure the product specifications till that validity of drug product (Rathore
and Winkle, 2009). This newer approach is called quality by design (QbD) as defined by
ICH Q8 (R2) document “a systematic approach to development that begins with predefined

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objectives and emphasizes product and process understanding and process control, based
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on sound science and quality risk management” (Guideline, 2009). Information gained
through QbD helps in establishing design space, specifications, and manufacturing controls.
The element of QbD include quality target product profile, risk assessment, critical
quality attributes, drug substance, polymers and/or excipients, amorphous/crystalline ratio,
dissolution, manufacturing process, quality risk management, design space and control
strategy (Kepert et al., 2016).
9.2. Critical quality attributes

As per ICH-Q8 (R2) critical quality attribute (CQA) is defined as “physical, chemical,
biological, or microbiological characteristic that should be within the appropriate limit range
or distribution to ensure the desired product quality”. In general, CQAs are considered
to be ascribing of the drug substance, excipients (polymers), and final drug products but
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might also include CQA of the drug product intermediates in various manufacturing steps.
The CQAs of a drug product may include those characteristics that affect purity, dose
strength, drug release profile, and storage stability, e.g., assay, impurity profile, accelerated
stability, dissolution rate, and amorphous/crystalline (A/C ratio), etc. More specifically, for
ASD, important CQAs are dissolution and A/C ratio. This is directly influencing the shelf
life of the final product. Intermediates ASD could be primary granules containing a solid
dispersion of drugs and polymers and/or excipients before blend with other ingredients
of the formulation such as diluents, lubricants, and glidants, etc. to formulate stable solid
dosage forms such as tablet and capsule (Charoo and Ali, 2013; Fonteyne et al., 2013;
Fonteyne et al., 2014).
9.3. Drug substance

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The properties of drug substance should be carefully assessed. Based on drug substance
properties the excipients, method, and process selection for ASD product will be
evaluated. The properties to be considered are solubility and miscibility in organic and
aqueous solvents, interaction with polymers, melting point, particle size and distribution,
micromeritic properties, and thermal stability. These properties determine manufacturing
ability, product performance, and long-term storage stability. For example, hot melt
extrusion and spray drying cannot be used for thermally labile drug molecules (Forster
et al., 2001).
9.4. Polymers/Excipients
Polymers play a major role in ASD formulations and it should meet regulatory requirements.
They should be falls in the category of food or pharmaceutical-grade materials which is
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considered “Generally Regarded As Safe” (GRAS) category. At FDA inactive ingredient

database, list of safe excipients/polymers and their percentage level of safely has
mentioned (Food and Administration, 2017). The suitable polymer selection is depending
on physicochemical properties of the drug, manufacturing process, and its manufacturability
as it is one of the determinants of CQAs of the ASD. The polymer properties also
to be concerned as a component of the ASD formulation are polymer type, molecular
weight, polydispersity nature, concentration or amount, number of the polymer in the
formulation, melting point and/or glass transition temperature (Tg), drug miscibility, solvent

solubility, particle size and distribution, hygroscopicity, compatibility with the drug and
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other excipients of the formulation, presence or absence of the intermolecular interactions

(chemistry of the polymer), mechanical properties and chemical stability (Al-Obaidi et al.,
2009). Drug to polymer ratio is selected based on polymer properties and it should be
convenient to process and allow for the intermediate also to be processed into tablet or
capsule dosage form. The biggest task of a solid dispersion is to maintain the drug in the
amorphous state in the final dosage form. This can be attained by using low drug strength
and high polymer levels. On the other hand, physicochemical interaction to be taken in
account to avoid unexpected outcomes of dosage form at the final level as thermodynamics
of crystallization/destabilization driving forces depend on the drug loading capacity, drug–
polymer solubility and miscibility, and its glass transition (Tg) (Baldrick, 2013).
9.5. Amorphous/Crystalline ratio (A/C ratio)

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Proven in vivo/in vitro performance of the ASD drug product is due to the availability of
drug is in completely or partially amorphous drug in these products when compared to
its crystalline form drug product. Additionally, in vivo performance of the ASD may be
related to A/C ratio and keeping that ratio entire of its shelf life would ensure persistent
pharmacological response. Hence, it is necessary to understand the formulation and process
parameters that could possibly conversion of A/C ratio in the final product (Rahman et al.,
2014). Meanwhile, monitoring of this ratio is also crucial during drug product development
as it can affect the formulation and/or process factors need to change and control. By the
same way, post approval monitoring of the ratio is also important as it can estimate when
product becomes unsafe/inefficacious to use. It may cause recalling of drug products from
market. The various analytical tools were available to monitor the A/C ratio on various level
of manufacturing and post marketing process. This is one of the specifications of ASD-based
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products in NDA/ANDA submission to the USFDA as a measure of safety and efficacy

of the product. Powder X-ray diffraction (PXRD) is the golden technique used to identify
and quantify the crystalline drug in the amorphous system. The technique is very simple
to handle and non-destructive, with the ability to identify crystallinity at the level as low
as 5%. As crystalline material shows strong diffractions with respective of their molecular
arrangement in the crystalline lattice, but amorphous material shows an amorphous halo and
diffuse diffraction pattern due to lack of crystalline order at the molecular level (Bhargavi
et al., 2017; Shah et al., 2012). For ASD, intermediate product is well mixed with other
excipients of the formulation, which is leading to determination of the A/C ratio, especially
for the low-dose drug. Apart from PXRD other techniques of spectroscopy such as Fourier
infrared, near infrared, or Raman spectroscopy in conjunction with chemometric methods
such as principle component analysis and partial least square analysis, which may use to
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predict and segregate the peaks of the drug from the excipients (Zidan et al., 2012).
9.6. Design space

According to ICH Q8 (R2) document, design space is “a multi-dimensional combination
and interaction of input variables (e.g., material attributes) and process parameters that have
been demonstrated to provide assurance of quality”. Working within design space is not
concluded a change of parameters because product will meet the defined quality. However,
any parameter moved out of the design space is considered as change and it initiates

regulatory post approval process. The design space is wider nature and robust to use, as
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it would accommodate wider variation in the process and/or formulation parameters. Risk
assessment, multivariate experimental design, literature, and prior experience/knowledge
contribute in defining the design space (Evans et al., 2019). Design space of the product can
be prepared through complex mathematical relationships. The process parameters studied
should be CPPs that have significant effect on the CQAs. On other side, material attributes
studied should be critical attributes of the drug substance (particle size, polymorphs,
impurity, etc.) and excipients (moisture level, particle size, molecular weight, etc.) that
would affect the CQAs of the ASD. CPPs help in defining and controlling the design
space. Practically, it may be easier to understand, develop and control design space of
individual unit processes of a multistep operation, and this approach would also provide
greater operational flexibility (Mishra et al., 2018). Various marketed products of ASD were
captured in Table 3.
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10. Future aspects and conclusion

Much pharmaceutical industry has evolved rapid use of ASDs for addressing bioavailability
issues associated with low solubility API. The main confront remains in ASD is chemical
or physical stability with limited data. Looking for solid state nature of solid i.e. crystalline
or amorphous by XRPD or DSC is not effective means of ASD analysis since it only
estimates instability; it does not predict it. Many researches are ongoing for prediction
and characterization of ASD compositions can quickly be screened and lead formulations
chosen that will reduce physical or chemical stability issues. With this protocol in place,
there may be a driver for many conventional formulations to switch to ASDs merely for
robustness purposes. Formulating amorphous API and associated concerns with molecular
and particle attributes changes may become obsolete, or at the very least, a fewer effective
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means of quickly getting drugs on the market. Introduction of QbD principles as laid out in
the ICH documents Q8, Q8 (R2) and Q9 allow for a rational drug product development with
well-controlled product intermediate and final product quality in the QbD paradigm. Solid
dispersion products are highly amenable to the utilization of novel technologies with respect
to the drug crystalline reversion and content uniformity throughout the shelf life.
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Fig. 1.
Biopharmaceutics classification system and formulation approaches for different classes of
drugs.
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Fig. 2.
Briefly captured details about ASD preparation methods and characterization methods.
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Fig. 3.
Basic concept of drug uptake from ASDs. From the solid state of ASDs containing
polymers, micelles, crystals and complex mixture of API in solution and colloidal API
emerges, from which the drug absorption through the intestinal membrane is enhanced. And
followed by three main concepts for dissolution from ASDs were depicted.
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Table 1
List and description of some recent studies employed on ASD.
Compound Polymers Method of Aim of the study Remarks Ref.

Pandi et al.
name preparation
Vemurafenib HPMCP HP-55, Eudragit L-100-55, Micro- Improvement of physical Study concluded all prepared ASD’s only Eudragit L-100-55 (Shah et al.,
HPMCAS-L precipitated bulk stability, dissolution and human and HPMCAS-L ASD's were found to be stable. HPMCAS-L 2013)
powder pharmacokinetic profiles ASD provided better dissolution results and fivefold increased
technology from its crystalline form
Itraconazole Polyvinyl pyrrolidone vinyl acetate Solvent Evaluation of storage stability Compare with PVPVA, HPMCAS showed good storage (Zhang et al.,
co-polymer88 and Hydroxy propyl evaporation stability at extended RH more than 60% which can be 2019)
methyl cellulose acetate succinate attributed to its higher glass transition temperature ad lower
hydrophobicity
Phenacetin Polyvinyl pyrollidone Solvent Estimation of kinetic solubility Non-linear kinetic parameters appeared on cold crystallization (Lapuk et al.,
evaporation of ASD prone to crystallization of Phenacetin based on molecular weight of the polymer 2019b)
Atorvastatin Pluronic F127 and Pluronic F68 Fusion method Optimization of bioavailability Improvement of solubility was observed either Pluronic F127 (Shaker et al.,
with reduced dose and and Pluronic F68 with 4.04 increased bioavailability compared 2019)
improvement of solubility with plain drugs
AZD0837 Plolyethylene oxide Hot melt Investigation of controlled Study revealed that, the molecule maintained its amorphous (Deshmukh et
extrusion release performance of caplet nature throughout the dissolution process and was maintained al., 2019)
shaped injection molded ASD in a super saturated state and stable as well
Curcumin Hydroxy propyl methyl cellulose E5 Solvent Elucidation of impact of HPMC HPMC E5 impacts the crystallization inhibition significantly (Fan et al., 2018)
and Eudragit E100 evaporation E5 on crystallization and maintained the amorphous drug concentration owed to
improvement of permeability hydrogen bond interaction between the curcumin and polymer
and improved the permeability by lowering of phospholipid
bilayer.
Darunavir Hydroxy propyl methy cellulose/ Coaxial electro Introduction of coaxial Study discussed about electrospraying technique and impact (Smeets et al.,
Polyvinyl pyrollidone spraying electrospraying technique and of polymers on molecule evaluated. Combination of these two 2019)
evaluation of encapsulation polymers was improved the drug loading capacity and gastro
efficiency resistant influence on the molecule.
Efavirenz Soluplus Spray drying Improvement of aqueous Experimentally obtained the phase diagrams by (Costa et al.,
solubility and bioavailability recrystallization of supersaturated API polymer solution. This 2019)
is used to determine the temperature composition phase

diagram by fast process spray drying. And employed to
evaluate the different drug loadings observed with different
thermal conditions
Etoposide Vitamin E TPGS with Solvent Investigation of solubility and Based on experimental research, above Critical micellar (Beig et al.,
Copovidone:Eudragit L-100 (60:20) evaporation permeability interplay when concentration (CMC) solubility of Etoposide increased linearly 2017)
using TPGS and amorphous and ASD allowed for super saturation. High level of
solid dispersion super saturation helped via ASD improved the drug in-vivo
permeability by supporting the P-gp saturation
Nifedipine Polyvinylpyrrolidone vinyl acetate Hot melt Investigation of different types Controlled instrumental parameters were selected for thermal (Mathers et al.,
(PVP/VA 64) extrusion of energy input affect the and mechanical energy input. Found that, both mechanical 2019)
stability and preparation of and thermal energy affect the crystalline state conversion
ASD's into amorphous and affected the level of mixing and degree
of homogeneity in ASD as well. Author concluded thermal
Page 22

name preparation
energy is more efficient than mechanical energy and that have
better stability
Ibuprofen Methacrylic acid ethyl acrylate co Hot melt Evaluation of effect of heat and Preparation of binary ASD's composed of polymer and drug, (Mathers et al.,
Pandi et al.
polymer type A, Eudragit L-100-55 extrusion shear rate on physico chemical minimized the level of degradation and found that stability 2019)
(EUD) properties of drug and excipient of drug was increased further. This is because polymer and
molecule subsequently buildup of sustained supersaturation
state
Griseofulvin Polyvinyl pyrrolidone vinyl acetate Freeze drying Evaluation of crystallization Observed significant improvement in dissolution and oral (Kawakami et
polymer tendency of molecule on absorption due to its high degree of supersaturation because al., 2019)
dissolution and oral absorption of high crystallization tendency. Turbidity measurement results
were revealed that, apparent phase separation concentration
increased in the presence of polymers.
Aripiprazole Kollidon 12 PF Hot melt Enhancement of solubility and Study revealed that, the molecule gave better dissolution (McFall et al.,
extrusion bioavailability by pH modulated results compare with plain API. However, formulations with 2019)
amorphous solid dispersion acidifier performed much better than formulations without
acidifier. It helps to improve the oral bioavailability.
Ketoconazole Poly(vinylpyrrolidone-co-vinyl- Hot melt Evaluation of impact of This study demonstrated the importance of polymers nature (Auch et al.,
acetate) extrusion molecular weight and PDI of on formulation. Results discussed that, minute changes of 2019)
polymer on drug dissolution molecular weight and PDI may influence supersaturation and
precipitation of the drug. Controlled parameters of HME are
making impact on drug dissolution.
Nevirapine HPMCAS, Hot melt Evaluation of ASD with pH Enteric polymers were used to avoid the influence of drug (Monschke and
hydroxypropylmethycellulose extrusion dependent soluble polymers to in gastric environment to improve the better physical stability Wagner, 2019)
phthalate and Eudragit L100-55. overcome limited bioavailability and dissolution performance. Solid dispersion made of enteric
due to gastric pH variability polymers were independent to gastric pH and exhibited
superior dissolution performance
Fenofibrate PVPK30, HPMC E6, HPMCE15 Solvent Development of novel solid Dissolution of pellets containing fenofibrate was found (Nguyen et al.,
evaporation dispersion-based pellets using significantly higher compared with plain drug and reference 2019)
one step process layering compound. Bioequivalence study was conducted in beagle
method dogs using validated assay method. Results concluded that
ASD pellets were equivalent to reference tablet.
Nobiletin Mixtures of methyl hesperidin Hot melt Novel application of methyl Nobiletin amorphous solid dispersion was prepared using (Iwashita et al.,
extrusion hesperidin as an excipient for methyl hesperidin by hot melt extrusion technique. The 2019)

hot melt extrusion prepared ASD was showed higher drug concentration and
improved dissolution rate up to 7.5 times. Permeability of
Nobiletin was predominantly increased and found that stable
up to 6 months in accelerated stability conditions.
Rivaroxaban Soluplus, Kollidon25 and Melt quenching Evaluation of physical stability In this study, Flory-Huggins lattice solution theory was applied (Kapourani et
copovidone approach and intermolecular interactions to build thermodynamic phase diagrams of ASD with different al., 2019)
in polymeric carriers via polymeric carriers. Study concluded that, intermolecular
thermodynamic modeling and interaction with moisture played important role for physical
molecular stability of prepared ASD's.
Felodipine PVP K29/K32, HPMC, HPMCAS- Super critical Evaluation of crystallization This study concluded that, these polymers were equally (Konno and
M fluid method tendency of molecule on effective on reduction of nucleation rate in the absence of Taylor, 2006)
dissolution and bioavailability moisture.
Page 23

name preparation
Glibenclamide Hypromellose acetate succinate Anti-solvent Mechanistic elucidation of The co-spray drying method was applied for preparation of (Ueda et al.,
addition method formation of drug-rich drug ASD and it significantly enhanced the dissolution which 2019)
nanodroplets by dissolution is lead to the formation of Glibenclamide rich amorphous
Pandi et al.
droplets.
Carvedilol β-cyclodextrin and hydroxypropyl-β- Complexation Enhancement of carvedilol Stable complexes formed which was confirmed from the (Yuvaraja and
cyclodextrin and kneading solubility by solid dispersion complexation constant of drug and the carriers. Solid state Khanam, 2014)
technique technique using cyclodextrins results confirmed the carvedilol has been converted into
complexation technique amorphous state. In-vitro results of prepared ASD showed
higher dissolution rate in phosphate buffer media with the pH
range of 6.8 and 7.4 than plain drug.

Page 24
Table 2
Characterization of amorphous solid dispersion with examples.
Techniques Principle Advantages Limitations Remarks Ref.

Pandi et al.
Thermal/
Calorimetric
Analysis
Differential When a sample undergoes a physical Suitable to measure Less sensitive to heat Kaushal et al. utilized to identify the glass (Kaushal and
scanning transformation, like a phase transition, more melting, Experimental capacity measurement forming ability of molecule. And they have Bansal, 2008)
calorimetry or less heat will need to flow to it than the settings are simple and suggested, if compounds have higher glass
reference material to maintain both at the same easily manageable forming ability it has low critical cooling
temperature. rates
Modulated Uses two simultaneous heating rates - a linear Complex and overlapping Strongly conditions Six et al. studied itraconazole-Eudragit (Six et al., 2003)
Differential heating rate that provides information similar to of thermal events dependent, Melting: E100 s using mDSC. They have identified
scanning standard DSC, and a sinusoidal or modulated are differentiated, Study Interpretation is abstruse, drug polymer miscibility and causes of
calorimetry heating rate that permits the simultaneous of phase separation, measurement is not precise causes instability of the ASD
measurement of the sample's heat capacity. accurate quantification of
amorphous phases
Dynamic Measurement of resultant strain that comes Non sample destructive Not suitable for Yang et al. exposed the temperature (Yang et al.,
mechanical from the applied oscillatory stress, and it builds technique, viscoelastic characterizing the low dependent miscibility of acetaminophen in 2011)
thermal analysis a function of the strain determined versus properties of polymers are viscous materials, poor poly (ethylene oxide) which increased from
frequency or temperature fetched by time-efficient stress control capacity 14% at 80 °C to 41% at 140 °C.
technique
Isothermal micro The constant assessment of the heat out flow Highly sensitive, shelf Tedious process takes hours Gill et al. employed isothermal (Gill et al., 1993)
calorimetry and cumulative amount of heat consumed or life and non-destructive to days to evaluate microcalorimetry (IMC) to procure the
produced at quite constant temperature by an process structural relaxation time.
instance
Spectroscopic
techniques
Solid state The excitation of nuclei when bombarded with Non-destructive, Minimal Lack of sensitivity, Forster et al. utilized solid-state 1H NMR (Forster et al.,
Nuclear Magnetic pulses of broad radio frequency radiation induces sample manipulation, Expensive, Difficulty to differentiate the molecular mobility 2003)
Resonance spin in nuclei and when nuclei relaxes back to Small sample size, Simple of quantification-chemical of indomethacin and nifedipine along
their equilibrium statesthe free induction decay sample preparation noise and signal over with their ASDs. They deduced that
results or produced as response. lapping the relaxation habits of nifedipine ASDs

remarkably altered as a function of
temperature, which explained the internal
stability of nifedipine ASDs compared to
indomethacin ASDs
Fourier transform The chemical bonds and functional groups of a Quantitative analysis, less accurate results and Rumondor et al. used FTIR spectroscopy (Chavan et al.,
Infrared sample at atomic level undergoes constant rate of applied for all states of the moisture presence may give to investigate the degree of mixing between 2017; Rumondor
technique vibration. When IR with continuous wavelength matter, Nondestructive and inaccurate results drugs and polymers in ASDs. Amorphous- and Taylor, 2010)
strikes the sample, a particular wave number is Small sample size amorphous phase separation was identified
absorbed by a specific bond and functional group in this technique
of the sample and absorbed spectrum is produced
by the detector.
Raman It is based on Raman effect: the inelastic Quantitative analysis, The Raman effect is very Tres et al. employed Raman spectroscopy (Tres et al., 2014)
spectroscopy collisions of sample molecules when interacts Nondestructive and Small weak. The detection needs imaging with multivariate curve resolution
with monochromatic laser beam generates the sample size, not interfered a sensitive and highly real-time to explore the dissolution
Page 25
Techniques Principle Advantages Limitations Remarks Ref.

scattered light which is responsible for the by water, highly specific optimized instrumentation; mechanism of ASD tablets. Homogeneity
construction of Raman spectrum. like a chemical fingerprint sample heating through the and phase separation can be identified by
of a material. intense laser radiation can this technique
destroy the sample or cover
the Raman spectrum.
Pandi et al.
Microscopic and
macroscopical
techniques
X-ray Powder The filtered and collimated rays of cathode ray Determine crystallinity Less interaction with lighter Nollenberger et al. had explained the (Nollenberger et
Diffraction tube are directed towards the sample which of the compound, Best elements, Relatively less practicability and advantages of using al., 2009)
produces constructive interference and diffracted method for phase analysis, sensitivity PXRD. He deduced that the PXRD
rays which satisfies nλ = 2d sin θ (Bragg's law). non-destructive measurements solely could not notice any
difference in formulations with or without
Eudragit R NE
Scanning electron Accelerated electrons in an SEM carry Three-dimensional and Expensive, large and must Ye et al. utilized SEM to explore the (Ye et al., 2016)
microscopy significant amounts of kinetic energy, and this topographical imaging be housed in an area free compleX arrangement of efavirenz solid
energy is dissipated as a variety of signals consumes less time to of any possible electric, dispersions and the particle size distribution
produced by electron-sample interactions when complete SEI, BSE and magnetic or vibration which found to be around 20 μm and
the incident electrons are decelerated in the solid EDS analyses. interference uniformly distributed.
sample.
Polarized light When polarized light hits the double refracting Non-destructive, easy to It is not suitable Telang et al. proposed that PLM might be (Telang et al.,
microscopy sample and produces ordinary and extraordinary operate and reproducible for agglomerates; sample a more appropriate tool to examine the 2009)
light rays perpendicular to each other. These rays recovery is little tedious physical stability of ASDs due to its high
are combined using constructive and destructive sensitivity when juxtaposed to XRD.
interference through analyzer to produce high
contrast image.
AFM It works in three steps surface sensing, detecting Highest lateral resolution Expensive, relatively slow Matthias et al. exercised AFM technique (Lauer et al.,
and imaging, using a sharp tip cantilever to scan up to 1 nm, it can scan time, which can lead to to examine the long-term stability of solid 2011)
over the surface of a sample. The attractive and identify the repeated thermal drift on the sample dispersions and concluded that developed
repulsive forces between the tip and the surface lattices on crystal structure method to quantify the de-mixing by phase
cause the cantilever to deflect towards or away and good comprehensive separation analysis.
from the surface respectively. Any of these slight understanding
deflections of cantilever are traced by deflections
of laser beam which mounted on the cantilever
are recorded by position sensitive photo diode
and generates accurate tonographic image.

Page 26
Table 3
Examples of commercially available medicines using solid dispersion technologies.
Product name Drug BCS Carrier Preparation method Company name Therapeutic Dosage Year of Ref.
Pandi et al.
class polymer category form approval

in FDA
Cesamet (US)/ Nabilone II PVP Solvent evaporation Valeant Cancer Capsule 1985 (Food and Administration,
CanemesAustria) 2006)
Onmel Itraconazole IV HPMC HME Merz Onychomycosis Tablet 2010 (Gupta et al., 2013)
Advagraf/ Astagraf Tacrolimus II HPMC Wet granulation Astellas Organ Capsule 2013 (Noble et al., 2018)
XL transplantation
Gris-Peg Griseofluvin IV PEG 6000 Melt extrusion Pedinol Fungal infection Tablet 1975 (Chiou and Riegelman,
1970)
Crestor® Rosuvastatin II HPMC Spray drying Astra Zeneca Hyperlipidemia Tablet 2002 (Vo et al., 2013)
Cymbalta Duloxetine II HPMCAS Not available Eli Lilly Depression and Capsule 2004 (Bymaster et al., 2003)
Anxiety
Kaletra Lopinavir/ IV PVP PME AbbVie AIDS Tablet 2005 (Corbett et al., 2002)
ritonavir
Eucreas/ Galvusmet Vildagliptin/ III HPC Melt extrusion Novartis Diabetes Tablet 2007 (Lu et al., 2014)
Metformin HCL
Intelence Etravirine IV HPMC HME J&J AIDS Tablet 2008 (Abramowicz et al., 2008)
Prograf Tacrolimus II HPMC Kneading, drying Astellas Organ Tablet 1994 (Woillard et al., 2011)
transplantation
Samsca Tolvaptan IV N/A Granulation Otsuka Hyponatremia Tablet 2009 (Ramesh et al., 2015)
Certican/ Zortress Everolimus III HPMC Co-precipitation Novartis Organ Tablet 2010 (Ardeshana et al., 2020)
transplantation
Lozanoc Itraconazole IV HPMCP Spray drying Mayne Fungal infection Capsule 2012 (Pérez-Ruiz et al., 2002)
Fenoglide Fenofibrate II PEG6000, Controlled SantorusVeloxis Hyperlipidemia Tablet 2007 (Ling et al., 2013)

Poloxamer 188 agglomeration, SD
Norvir Ritonavir IV PVP HME Abbvie AIDS Tablet 2010 (Schouten, 1996)
Incivek Telaprevir II HPMCAS Spray drying Vertex Hepatitis Tablet 2011 (Kwong et al., 2011)
Zelboraf Vemurafenib IV HPMCAS Microprecipitation Roche Cancer Tablet 2011 (Shah et al., 2013)
Kalydeco Ivacaftor II/IV HPMCAS Spray drying Vertex Cystic fibrosis Tablet 2012 (GUNTAKA and
LANKALAPALLI, 2019)
Noxafil Posaconazole II HPMCAS SD, HME Merck Fungal infection Tablet 2013 (Hens et al., 2016)
Viekira™ (US)/ Ombitasvir/ II HPMCAS/ Melt extrusion Abbvie Heapatitis C Tablet 2014 (Solanki et al., 2019)
Viekirax® (EU) Paritaprevir/ TPGS/
Ritonavir Propylene
Page 27
Product name Drug BCS Carrier Preparation method Company name Therapeutic Dosage Year of Ref.
class polymer category form approval
in FDA
Glycol
Monolaurate
Pandi et al.
Isoptin SR Verapamil HCl II HPC/HPMC HME Abbott HTN Tablet 1997 (Vajna et al., 2011)
Mesulid fast Nimesulide II B-CD β-CD Novartis Pain Tablet Not filed (Patel, 2016)
Rezulin Troglitazone II HPMC HME Pfizer Diabetes Tablet 1997 (Ito et al., 2010)
Sporanox Itraconazole IV HPMC Spray drying Janssen Fungal infections Tablet 1992 (Thiry et al., 2017)

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Published in final edited form as:

Amorphous solid dispersions: An update for preparation,

Chennai 600078, India

recurrently for poorly soluble pharmaceutical compounds. In an ASD, the solubility of

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

2. Amorphous solid dispersion

2.2. Amorphous solid dispersion

Bioavailability of drug can be ultimately improved by amorphous solid dispersion when

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

4. Selection of polymers in ASD

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

an ability to improve the bioavailability by enhancing the permeation of drug through GI

membranes (He and Ho, 2015).

5. Methodologies for ASD

discussed in this review.

7. Mechanism of ASD on increasing bioavailability

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

and crystallization occurs spontaneously. Amorphous compounds have desired properties of

Gconf = Hconf (T ) + Sconf (T )

in dissolution of ASD (Schittny et al., 2020).

7.1. Carrier controlled release

7.2. Dissolution controlled release

7.3. Drug controlled release

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

8. Stability of amorphous solid dispersion

estimate real-time stability (Committee, 2003)). In addition to the stability assessment of

8.1. Factors affecting stability

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

8.2. Thermodynamic aspect

8.3. Kinetic Aspect: Molecular mobility

8.4. Effect of temperature on molecular mobility

8.5. Moisture effect on mobility

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

9. Regulatory considerations in development of ASD

9.1. Quality by design

The traditional approach of pharmaceutical development may be called quality by testing

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

9.2. Critical quality attributes

9.3. Drug substance

considered “Generally Regarded As Safe” (GRAS) category. At FDA inactive ingredient

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

other excipients of the formulation, presence or absence of the intermolecular interactions

9.5. Amorphous/Crystalline ratio (A/C ratio)

products in NDA/ANDA submission to the USFDA as a measure of safety and efficacy

9.6. Design space

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

10. Future aspects and conclusion

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

structure forming ability. Cryst. Growth Des 17, 1480–1483.

Int. J. Pharm 231, 131–144. [PubMed: 11755266]

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

Elgindy N, Elkhodairy K, Molokhia A, Elzoghby A, 2011. Lyophilization monophase solution

Pharm. Clin. Res 12, 356–363.

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

Hens B, Corsetti M, Brouwers J, Augustijns P, 2016. Gastrointestinal and systemic monitoring of

Sci 105, 2904–2912. [PubMed: 27178739]

Iwashita M, Hashizume K, Umehara M, Ishigami T, Onishi S, Yamamoto M, Higashi K, Moribe K,

Drug Delivery Therapeut 10, 173–177.

Int J Pharm. Author manuscript; available in PMC 2021 December 21.

Lapuk S, Mukhametzyanov T, Schick C, Gerasimov A, 2019a. Kinetic stability of amorphous

amorphous solid dispersions, Cryst. Growth Design

without sacrifice of intestinal membrane permeability. Mol. Pharm 9, 2009–2016. [PubMed:

Newman A, Nagapudi K, Wenslow R, 2015. Amorphous solid dispersions: a robust platform to