Artículo 1
Artículo 1
Artículo 1
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Int J Pharm. Author manuscript; available in PMC 2021 December 21.
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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). [email protected] (W. Khan), [email protected] (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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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
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.
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.
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.
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
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.
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
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.
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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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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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).
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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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).
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
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).
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).
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).
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).
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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solubility, particle size and distribution, hygroscopicity, compatibility with the drug and
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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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predict and segregate the peaks of the drug from the excipients (Zidan et al., 2012).
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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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
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
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)
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.
Table 2
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
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.
Table 3
Product name Drug BCS Carrier Preparation method Company name Therapeutic Dosage Year of Ref.
Pandi et al.
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)