Online - 2455-3891

Vol 12, Issue 3, 2019 Print - 0974-2441

Research Article

SOLID DISPERSIONS: RESUSCITATING ORAL DELIVERY OF HYDROPHOBIC DRUGS

RUCHI AGRAWAL1*, ABID RAZA2, OM PRAKASH PATEL2

1
Department of Pharmaceutics, Krupanidhi College of Pharmacy, Bengaluru - 560 035, Karnataka, India. 2Student, Krupanidhi College of
Pharmacy, Bengaluru - 560 035, Karnataka, India. Email: [email protected]
Received: 25 September 2018, Revised and Accepted: 24 November 2018

ABSTRACT

Objective: This review article explores solid dispersions (SDs) as one of the suitable approaches to formulate poorly water-soluble drugs. The objective
of this review on SD techniques is to explore their utility as a feasible, simple, and economically viable method for augmentation of dissolution of
hydrophobic drugs.

Methods: Various types of SDs are classified and compared. Use of surfactants to stabilize the SDs and their potential advantages and disadvantages has
been discussed. Different techniques for preparing and evaluating SDs are appraised along with discussions on scalability and industrial production.
Review of the current research on SD along with future trends is also offered.

Results: Based on the various researches, SDs offer an efficient means of improving bioavailability while concurrently contributing to lower toxicity
and dose-reduction.

Conclusion: Solid-dispersions have been and continue to be one of the key technologies for solving the issue of poor solubility for newer hydrophobic
molecules which are being discovered. This would give a new lease of life for such drugs enabling them to be delivered in an effective way.

Keywords: Amorphous, Dissolution rate, Hydrophobic drugs, Solid dispersions, Solubility enhancement.

© 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2019.v12i3.29948

INTRODUCTION chemical modifications such as changes in pH and alteration in the salt

form have also been suggested.
Active pharmaceutical ingredients (APIs) have been classified on the
basis of their water solubility and permeability through the intestinal In this review, the description of SDs as a simple and cost-effective tool
mucosa as per the biopharmaceutical classification system (BCS) [1]. for dissolution enhancement has been discussed.
The chief factors which affect absorption of APIs through intestinal
mucosa after oral administration are their rate of dissolution, solubility, SDS
and permeability. The challenge lies with APIs belonging to BCS Class II
or Class IV. In general, the rate limiting step for absorption of the drugs SDs are solid state systems where one or more APIs are mixed intimately
in these classes is the low dissolution velocity emerging from low with an inert substance which can be a hydrophilic polymer(s) or
solubility. matrix forming agents [3]. The nature of the carrier can be crystalline
or amorphous. The augmentation in the rate of dissolution of APIs
Nearly, more than 90% of drugs are orally administered. The made into SDs is credited to following reasons [4]:
bioavailability of APIs is directly related to their solubility or rate • Molecular dispersions result in the reduction of particle size and
of dissolution in water and/or biological fluids which are primarily increase in surface area.
aqueous in nature. Nearly, one-third of all under development new • Conversion of crystalline APIs into amorphous systems results in the
drugs/chemical entities are poorly water-soluble and are, therefore, enhancement of the rate of dissolution. This is attributed to the lack
difficult to formulate. Hydrophobic drugs often encounter problems of energy requirements during the dissolution process to break up
such as poor absorption which may lead to inadequate and mutable the amorphous structure, unlike the organized crystalline state.
bioavailability. Hydrophobic APIs will display absorption kinetics based • Increase in wetting properties due to a decrease in interfacial tension,
on the rate-limiting step of dissolution, and those APIs with insufficient in case of carriers with surface activity.
permeability will demonstrate permeation - rate limited absorption • In contrast to APIs, SDs exhibit increased porosity.
kinetics [1]. Noyes–Whitney equation suggests that the aqueous • Hydrogen bonding effect among APIs and the carrier results in the
solubility of an API is directly related to the its rate of dissolution cosolvent effect.
and consequently it is a significant variable that regulates the rate of Categorzation of SDs.
dissolution and thereby the absorption [2].
Based on the carriers used
To increase their solubility, numerous methodologies have been This is depicted in Fig. 1.
suggested such as alterations in physical form. These include a decrease
in particle size to micrometers/nanometers and use of complexing First generation SDs
agents, cosolvents, solubilizers, and surfactants. In addition, modification Carriers which are crystalline in nature are mixed with APIs to make
of crystal habit has been suggested which includes changing it to a SDs. Urea and sugar were amongst the first carriers used for the
more soluble polymorphic form or changing the crystalline form to formulation of SDs [5]. However, such SDs have the serious drawback of
an amorphous form solid dispersion (SD). Further, drug dispersion having crystalline structures which are thermodynamically stable and,
in hydrophilic carriers, formulation of lipid-based dosage forms and therefore, have greater energy needs for the disruption of the system
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Asian J Pharm Clin Res, Vol 12, Issue 3, 2019, 213-217

substitutional solid solutions, the solute molecules substitute the

solvent molecules in the crystal lattice. While in the interstitial solid
solutions, the dissolved molecules occupy the interstitial spaces
between the solvent molecules in the crystal lattice. Examples include
solid solutions of methyltestosterone, hydrocortisone acetate in the
matrix of PEG 6000 [9].

In 1965, Goldberg et al. elucidated the advantages of solid solutions as

compared to eutectic mixtures [10]. He mentioned that release of the
drug is faster from solid solutions as the dissolution process does not
consume the energy needed to disrupt the crystalline forms.

Based on the miscibility of drug and carrier

Fig. 1: Categorization of solid dispersions based on carriers Immiscibility in fluid phase
employed
In certain cases, where API and carriers are immiscible in their fluid
phase, they may not demonstrate the desired miscibility even on
into solution. This adversely affects the release of a drug at a faster rate. solidification. Enhancement in dissolution rate of these type of drugs
Kalaiselvan et al. formulated SDs of albendazole to using crystalline can be done through alteration in the morphology of the APIs and/or
carriers such as urea, polyethylene glycol (PEG) 6000, and poloxamer carriers due to changes in physical structure. The rate of solidification
407 and achieved significant improvement in the dissolution profile of and the rate of crystal formation are the critical parameters that govern
albendazole [6]. whether crystalline or amorphous SDs are formed.

Second generation SDs Miscibility in the fluid phase

Amorphous carriers are the excipients of choice to formulate these SDs. As both drugs and polymers are miscible in a fluid state, phase
Some of them include synthetic polymers such as hydroxypropyl methyl separation is expected (i.e., may or may not) during solidification,
cellulose, ethyl cellulose, polymethacrylates, polyethylene oxides, thereby influencing the structure of SD.
polyvinylpyrrolidone (PVP), and naturally derived polymers such as
starch derivatives like cyclodextrins. These result in an amorphous Methods for preparation of SD
product which is thermodynamically less stable and releases drugs at a The various methods are classified in Fig. 2.
faster rate compared to their crystalline counterparts. Sharma and Jain
have prepared SDs of carvedilol with amorphous carrier PVP K 30 using Kneading technique
the solvent evaporation method [7]. This is a simple method where drug and the polymer (carrier) are
mixed in a predetermined ratio and kneaded with the solvent resulting
Third generation SDs in the formation of a paste formed that is dried and sieved.
To prepare these SDs, usually, a surfactant or a blend of polymers or
a blend of surfactants and polymers are employed as carriers which SDs of indomethacin with lactose monohydrate and different
exhibit self-emulsifying properties. Surfactants such as inulin, glyceryl polymers -polyethylene oxide - 6000, hypromellose, PVP, and
behenate, and poloxamer 407 have been used as carriers in many β cyclodextrins  -  were prepared through the kneading method.
preparations to enhance the dissolution profile of a drug. They are A significant improvement in the dissolution and flow properties over
advantageous as the presence of surfactants prevents recrystallization raw indomethacin was observed [11]. This technique was successfully
and additionally enhances wettability and hence the dissolution employed to augment the rate of dissolution of the hydrophobic drug,
rate. Patel and Joshi evaluated surfactants and their combinations as meloxicam using poloxamer 188 [12].
effective carriers in preparation of SDs [8].
Melting/fusion technique
Based on solid-state structure This involves melting of the carrier and the addition of the drug into the
Eutectic mixtures melted carrier with continuous mixing. The drug melts inside the heated
A physical blend of two or more components that tends to reduce carrier, and a homogenous melt mass is obtained [13]. The fused mass is
melting points when mixed in certain proportions leading to the cooled rapidly and kept in desiccating chamber for the predetermined
formation of a mix that has melting point lower than the individual time. The solidified mass is grinded, milled, and sieved. Revaprazan-
components is called a eutectic mixture. This was first used in context loaded SDs were prepared using hydroxypropylmethylcellulose which
resulted in a significant enhancement of its dissolution property [14].
with SDs by Sekiguchi and Obi in 1961 [5]. In SDs composed of a eutectic
The method shows the benefits of being simple and economical and does
blend, the API and the carrier are present as fine particles. This leads
not require any sophisticated instrumentation. However, its application
to an enormous increase in surface area and the enhancement rate of
is restricted to the combination of drug and carrier where both have
dissolution of the API. Sulfathiazole is known to be first formulated by
nearly the same melting point and are stable at temperatures near their
this technique with urea as a carrier [3].
melting points. The cooling speed and temperature of the drugs and
carriers are critical factors in obtaining a homogenous product.
Solid solution
The SDs which are miscible in liquid, as well as the solid state, are Solvent evaporation method
termed as solid solutions. Based on the degree of miscibility of the The method involves choosing a solvent that has the capacity to dissolve
API and the carrier, solid solutions are of two types; continuous and drugs as well as the carriers. The API and the carrier are dissolved in
discontinuous solid solutions. In continuous solid solutions, the two the least possible volume of solvent with continuous stirring in two
components are miscible in the solid state in all proportions, whereas, different containers. The drug solution is added to the carrier solution
in discontinuous solid solutions, the components are immiscible at with continuous stirring. The solution is then evaporated under reduced
intermediate composition, but miscible at the extreme of composition. pressure to yield dry product [15]. The dried mass is crushed and sieved
and stored in desiccators. This method has the advantage over the melting
On the basis of the molecular size of the two components, the method that the drug is not exposed to higher temperature. This method
solid solutions are classified as substitutional and interstitial. In was employed to prepare SD of carbamazepine using PVP combined

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Asian J Pharm Clin Res, Vol 12, Issue 3, 2019, 213-217

Fig. 2: Various methods for preparing solid dispersions

with either Gelucire 44/14 or Vitamin E TPGS. The SDs showed higher range. In addition, it offers multiple advantages including the fact that
dissolution rate as compared to pure carbamazepine [16]. supercritical carbon dioxide can be removed and that carbon dioxide
is non-toxic and safe for patients even if some traces are left behind.
Sometimes, a combination of melting and solvent method can be Itraconazole was formulated into SD using supercritical fluid technique
employed using hypromellose, Pluronic F-127, and L-ascorbic acid [23]. Similar
In this case, the API is dissolved in a solvent in which it is freely soluble, attempts were made by researchers for poorly soluble API cefuroxime
the carrier is melted, and the API solution is added into the melt of the axetil using hypromellose and polyvinyl pyrrolidone as carriers [24].
solid carrier. This blend is finally evaporated to yield a clear solvent-
free film. The drying of the film is continued until it attains a constant Evaluation of SD
weight. This technique has the benefits of melting technique as well The evaluation is carried out by studying the effect on the dissolution
as solvent evaporation methods. This method is particularly useful for rate of drug after being formulated into SDs. In addition, solid-state
drugs that are thermolabile or have high melting points, but it is not characterization of the SDs must be done and compared with that of
suitable for drugs with a low therapeutic dose (below 50 mg). pure drug. The details of these evaluation tests are discussed below.

Lyophilization method Comparative dissolution rate studies

This method is generally used as an alternate to the solvent evaporation
This is done by comparing the in vitro dissolution release profiles of
method. Similar to the solvent evaporation method, this method also
the marketed product or pure drug, the physical mixture of drug and
involves the choice of a common solvent in which the drug and the
polymer used in SD and the SD itself. For immediate release products, a
carrier are dissolved in a predetermined ratio. The solution containing
model-independent approach can be followed which involves calculation
the drug and the carrier is frozen and subjected to lyophilization where
of difference factor (f1) and similarity factor (f2) between two dissolution
the frozen mass directly sublimes, and a porous SD is obtained. This
profiles following dissolution method [25]. Dissolution conditions can
is advantageous over solvent evaporation as it offers minimal thermal
be chosen based on the specifications recommended in the United States
stress and chances of phase separation while the solvent is being
Food and Drug Administration (US FDA) database or official books.
removed. Dissolution enhancement of glyburide was achieved using
this technique using different grades of PEGs as polymers [17]. SD of
efavirenz - PVP K-30 produced through the lyophilization technique Solid state characterization
resulted in significant solubility enhancement of efavirenz [18]. This is performed by employing the following techniques:
a. Differential scanning calorimetry (DSC)
Melt extrusion method b. X-ray diffraction study (XRD)
This method employs a corotating twin screw extruder. Here, the drug c. Scanning electron microscopy (SEM).
and the carrier are mixed together at their melting temperatures and d. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS)
the mix is extruded at a high rotational speed. Three processes, namely e. Residual solvent content determination
melting, homogenizing and then extrusion takes place simultaneously, f. Effect of aging.
and the product is shaped as desirable solid dosage form.
DSC
This technique involves a very brief exposure of the drug-carrier mix DSC is done to comprehend the thermal behavior of the product [26].
to an elevated temperature for a period of about one min. This enables This includes heating of samples at a predetermined rate which is mostly
even thermolabile drugs to be processed without being degraded. SD 10°C/min, till their melting point. The height of endothermic peak and
formulation of antiulcer drug lafutidine was successfully formulated heat of fusion is studied, and the physical mixture and the pure drug are
using hot melt extrusion (HME) technique, and it was demonstrated that compared. Any reduction in endothermic peak suggests partial conversion
the SD of lafutidine performed better with immediate drug release as of the crystalline drug into amorphous and the complete disappearance of
compared with pure lafutidine [19]. Agrawal et al. developed SDs using endothermic peak suggests total conversion of the drug from crystalline
HME technology with a scale up from mini scale to clinical scale [20]. to amorphous form. This polymorphic transition is favorable as it leads to
faster dissolution rate due to reduced energy requirement for breaking the
Electrospinning method disordered molecular structure in the amorphous product as compared to
This method involves preparation of solid fibers by passing drug carrier the highly ordered lattice in the crystalline product.
melt or drug carrier blend in a fluid state through nozzles of millimeter
scale. A strong electrostatic field is applied over a capillary which is X-ray powder diffraction (XRPD)
attached to vessel which contains the aforesaid drug-carrier fluid blend XRD is a critical tool used for the study of crystal structures and atomic
or melts. This method is advantageous as it is can yield fibres in nano spacing [27]. The scattering of X-rays from atoms produces a diffraction
range, and it is simple and economical to perform. Researchers have pattern that is characteristic of their arrangement. Monochromatic
made successful attempts to produce SDs of ketoprofen as nanofibers X-rays are produced by the cathode ray tube is focused toward the
using PVP as the carrier [21]. Similarly, SDs of hydrophobic API powder sample. The rays are diffracted which are characteristic of the
piroxicam were prepared using hypromellose and nanofibers were crystal structure of powder sample. These diffracted rays are sensed
produced using the electrospinning method [22]. and counted. Physical characterization of SD is done by studying the
absence of peak of crystallinity.
Supercritical fluid method
This method uses the principle of precipitating out drug-carrier blends The detection is based on Bragg’s law which says that radiation of
to form a common solvent using carbon dioxide as an anti-solvent. This wavelength λ incident on a series of planes with periodic spacing d will
approach is beneficial as it gives products in the micron to submicron be diffracted through an angle θ where,

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nλ=2 sinθ HME

HME is enormously adaptable for making industrial-scale SD [33].
SEM The chief benefit is that solvents are not needed. This circumvents the
SEM technique enables the study of sample’s surface topography and possibility of any residual solvent which may hamper stability and shelf
composition [28]. In this technique, the double-sided carbon tape is life. For example, in research work, miconazole SDs were prepared by
attached on aluminum stubs, and powder sample is sprinkled onto the HME. Miconazole was dissolved with the PEG portion of the copolymer
tape. The aluminum stubs are positioned in the vacuum chamber, and or was yielded as crystals in the identical or a dissimilar polymorph as
the morphological portrayal and surface characteristic of the sample the starting substance. The kinetic miscibility was found to be greater
are studied using the electron beam. for the HME-SDs produced from solutions that were pre-heated in
comparison with the spray-dried formulations. Furthermore, greater
DRIFTS amount of drug was incorporated into HME-SD than the spray-dried
Drug carrier interaction studies can be performed through this product [34].
technique. This is done using an FTIR spectrometer equipped with a
diffuse reflectance attachment and a data station [29]. This involves
preparation of KBr pellets after mixing it with the sample to be analyzed
Filling of semi-SDs into hard capsules
and scanning it at a wavelength range from 4000 to 400 cm-1. The spectra Semi-SDs are often tacky and pose a problem of handling and storage.
obtained are characteristic of the atomic arrangement in molecules. Stability problems are also seen in such formulations. A facile remedy
If the characteristic peaks of the drug and polymer are present in SD, for this problem is the direct filling of the liquid/semisolid melt of SD
it indicates that the drug and the polymer do not have any chemical into hard capsules. Once filled by means of mechanical and automated
interaction and will not alter each other’s stability. filling devices such as dosators, the melt solidifies into the capsules. This
circumvents the additional process of pulverization of the hardened
Residual solvent content determination mass, which speeds up production as well as reduces the chances of
This is required where organic solvents are being used for the changes in the crystallinity of the SD on grinding. For example, in a
preparation of SD to ensure that they are present in quantities lower research work, SDs of sparingly water-soluble drug amlodipine besylate
than their toxicity levels [30]. This is achieved using Karl Fischer were prepared and converted into a semisolid mass [35]. This mass
titration and thermal gravimetrical analysis. was then filled in hard gelatin capsules. The results showed improved
dissolution with a shortening of the lag time which meant a subsequent
Aging effect improvement in bioavailability.
The SD is stored at 30°C/65% RH for 3 months, and the dissolution rate
profile is performed to see the effect of aging in drug release. DSC and CONCLUSION
XRPD studies are performed and compared with the freshly prepared The paradigm shift occurring in the pharmaceutical industry worldwide
product to observe any change in the crystal structure. is the refocusing of efforts and financial resources into the development
of formerly neglected poorly water-soluble drugs for oral drug delivery.
Scalability and industrial applications
SD has been one of the key technologies driving this shift. As newer
SDs have been reported to have drawbacks with respect to their
hydrophobic molecules are discovered, instead of being discarded in
large-scale preparation due to the onerous processes of preparation
the pipeline they are being given a new lease of life through innovative
involving careful and subtle adjustments during their developmental
technologies as SDs. The synthesis of better excipients, polymers,
stages. Furthermore, concerns about the stability of the API within
and surfactants will offer many new avenues for the progress and
its vehicle are a major issue which impacts the shelf-life of the
development of better and novel SDs. With newer strategies employed,
product. However, on the positive side, efforts to overcome these and with a deeper understanding of the molecular and thermodynamic
hurdles have yielded promising results. The techniques to improve architecture, more stable, viable, effective, and feasible SDs can be
industrial application, scalability along with stability are discussed prepared.
below:
ACKNOWLEDGMENT
Capsugel® technology
Authors express their sincere thanks to The Management, Krupanidhi
It was innovated by bend research as a pioneering technology which
Group of Institutions for supporting the work through Krupanidhi
employed a spray-dried dispersion (SDD) method [31]. It presented a
Research Incubator Centre program under Krupanidhi College of
single-phase, amorphous molecular dispersion of API in a polymeric
Pharmacy and Accendere: CL Educate Ltd. Authors also extend sincere
matrix where the API is molecularly dissolved within a solid mass.
gratitude to Dr. Arshad Bashir Khan, Professor Krupanidhi College
SDDs were acquired by adding API and polymer to an organic solvent
of Pharmacy, for his expert guidance and contribution toward the
and then spray-dried. The process parameters were selected in such
manuscript.
a way so as to ensure that the solvent evaporated rapidly from the
globules, permitting inadequate time for phase separation or crystal
AUTHORS’ CONTRIBUTIONS
formation. SDDs have revealed enduring stability supplementing
their established results in solubility enhancement, simplistic Mrs. Ruchi Agrawal, contributed 46%, Mr. Abid Raza contributed 34%
scale-up, and admirable manufacturing capability. Expiration dates and Mr. Om Prakash Patel contributed 20% toward the preparation of
extending beyond 2 years have been reliably exhibited with SDDs. the manuscript of this review article.
Manufacturability has been consistently exhibited at levels ranging
from milligrams up to tons. CONFLICTS OF INTEREST

All the authors declare that they have no conflicts of interest.

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