Liquisolid compacts: A novel
approach to enhance the dissolution
Jignesh Solanki*, Dhiren
Daslaniya, Ghanshyam Patel, Bhavin Bhimani, Upendra Patel, Darshan Kamani
Arihant School of Pharmacy
& BRI, Uvarsad, Gandhinagar-382421.
*Corresponding Author E-mail:
jigneshksolanki@gmail.com
Liquisoild technique is a novel
concept for delivery of drugs through oral route. This approach of delivering
drugs is suitable mostly for lipophilic drugs and poorly or water insoluble
drugs. This approach is suitable for immediate or sustain release
formulations. Design and formulation of this approach is prescribed according to
new mathematical model given by Spires et al. Increasing the solubility by
using a non-volatile solvent which is suitable for drug, their by dissolving
the drug in the non volatile solvent and this is termed as liquid medicament .
Blending the liquid medicament with mixture of carrier and coating material,
liquid medicament can be converted into non adhere, dry looking powder with
acceptable flow properties and compression behavior using suitable excipients
and tabletting by direct compression method.
KEYWORDS: Liquisolid tablets, Dissolution
enhancement, coating material, carrier and solvents
INTRODUCTION:
Oral drug delivery is the
preferred way of administration for most of the active drug molecules due to
its several advantages like greater flexibility in design and high patient
compliance.1 Because of greater stability, accuracy in dose, easy of
production, formulation in the form of tablets is the preferred oral dosage
form. But the poor dissolution rate of water insoluble drugs is the major problem
for pharmaceutical formulators to prepare in the form of tablets.2
It is prerequisite for active ingredient in solid dosage form must undergo
dissolution to get absorb from gastrointestinal tract. The rate limiting step
for most of the pharmaceutical formulations is dissolution. Quality control can
be ensured for a formulation of different batches by determining in vitro dissolution
study. Bioequivalence can also be estimated under certain conditions.3,
Major rate limiting step for class II and IV is dissolution.4
Drug substances are considered
highly soluble when the largest dose of compound is soluble in < 250ml of
water over a range of pH from 1.0 to 7.5. In contrast, compounds with
solubilities below 0.1mg/mL face significant solubilization obstacles and often
even compounds with solubilities below 10mg/mL present difficulties related to
solubilization during formulation
The Biopharmaceutical
Classification System (BCS) groups poorly soluble compounds as Class II,
compounds which feature poor solubility, high permeability and Class IV,
compounds which feature poor solubility and poor permeability respectively.
Aqueous solubility of a drug can be a critical limitation to its oral
absorption. Lipophilic molecules, especially those belonging to the
biopharmaceutical classification system (BCS) class II and IV, dissolve slowly,
poorly and irregularly and hence pose serious delivery challenges, like
incomplete release from the dosage form, poor bioavailability, increased food
effect, and high inter-patient variability .5
To enhance these properties like
absorption, dissolution which are rate limiting step for lipophilic or poorly
soluble drugs, different approaches have been designed with required
modification in figure 1.6
In past, Liquisolid compacts are
derived from “powdered solutions, An past technique based on conversion of a
liquid medicament to nonadhere dry appearance powder which adsorb the
medicament onto silicas of large specific surfaces.7,8 These
preparations were analyzed by dissolution studies but because they are present
in the form of powder dispersion they could not be compressed into tablets.
There after studies based on powder solutions, with direct compression
enhancers like microcrystalline cellulose were added in solid dispersion to
improve compressibility of systems.9,10
Figure 1: Solubility enhancement as per BCS
classification
It is
believed that better bioavailability of poorly soluble drugs could be achieved
when drug is
present in solution as in liquisolid formulations.11 The concept of
Liquisolid compacts can be used to formulate liquid medication such as oily
liquid drug and solutions or suspensions of water-insoluble solid drugs in
non-volatile vehicles, into acceptably flowing and compressible powders. Using
this new formulation technique, a liquid medication may be converted into a
dry-looking, non-adherent, free flowing and readily compressible powder by a
simple blending with selected powder excipients referred to as carrier and
coating materials. Various grades of cellulose, starch, lactose, etc, may be
used as the carrier, whereas a very fine particle size silica powder may be
used as the coating material.12
Besides
drug release enhancement, the liquisolid approach is a promising technique
because of the simple manufacturing process, low production costs, and the
possibility of industrial manufacture due to the good flow and compaction
properties of the liquisolid formulations.13
Classification
a.
Based on
the type of liquid medication contained therein, liquisolid systems may be
classified into three subgroups:
1) Powdered drug solutions
2) Powdered drug suspensions
3) Powdered liquid drugs
The first two may be produced
from the conversion of drug solutions or (e.g. prednisolone solution in
propylene glycol) or drug suspensions (e.g. gemfibrozil suspension in
Polysorbate 80), and the latter from the formulation of liquid drugs (e.g.
clofibrate, valproic acid, liquid vitamins, etc.), into liquisolid systems.
b.
Based on
the formulation technique used, liquisolid systems may be classified into two
categories, namely,
1) Liquisolid compacts
2) Liquisolid microsystems
Liquisolid compacts are prepared
using the previously outlined method to produce tablets or capsules, whereas
the liquisolid microsystems are based on a new concept which to produce an
acceptably flowing admixture for encapsulations.14
ADVANTAGES OF LIQUISOLID SYSTEMS
• Number of water-insoluble solid drugs
can be formulated into liquisolid systems.
• Can be applied to formulate liquid
medications such as oily liquid drugs.
• Better availability of an orally
administered water insoluble drug.
• Lower production cost than that of
soft gelatin capsules
• Production of liquisolid systems is
similar to that of conventional tablets.
• Can be used for formulation of liquid
oily drugs
• Exhibits enhanced in-vitro and
in-vivo drug release as compared to commercial counterparts, including soft
gelatin capsule preparations.
• Can be used in controlled drug
delivery.
• Drug release can be modified using
suitable formulation ingredients
• Drug can be molecularly dispersed in
the formulation.
• Capability of industrial production
is also possible.
• Enhanced bioavailability can be
obtained as compared to conventional tablets.15-18
LIMITATIONS:
•
Low drug loading
capacities.
• Requirement of high solubility of
drug in non-volatile liquid vehicles.18-19
APPLICATIONS:
• Rapid release rates are obtained in
liquisolid formulations
• These can be efficiently used for
water insoluble solid drugs or liquid lipophilic drugs.
• Sustained release of drugs which are
water soluble drugs such as propranolol hydrochloride has been obtained by
the use of this technique.
• Solubility and dissolution
enhancement.
• Designing of controlled release
tablets.
• Application in probiotics.20-21
THEORY OF SOLUBILITY ENHANCEMENT:
The
mechanisms by which the liquisolid compacts show increased solubility and hence
bioavailability include; an increased surface area of drug available for
release, an increased aqueous solubility of the drug, and an improved wettability of the
drug particles.22 When the drug is dissolved or dispersed in a
liquid vehicle it is located in the powder substrate still in a solubilized,
molecularly dispersed state. Therefore, the surface area of drug available for
release is much greater than that of drug particles within directly compressed
tablets. The drug dissolved in the liquid vehicle is incorporated into a
carrier material which has a porous surface. The liquid initially absorbed in
the interior of the particles and is captured by its internal structure, and
after the saturation of this process, adsorption of the liquid onto the
internal and external surfaces of the porous carrier particles occur. Both
absorption and adsorption take place.23 Here at the solid/liquid
interface between an individual liquisolid primary particle and the release
medium, it is possible that, in this microenvironment the amount of liquid
vehicle diffusing out of a single liquisolid particle together with the drug
molecules increases the aqueous solubility of the drug.24
The liquid vehicle (Nonvolatile
solvent) present in the liquisolid system can either act as surface active
agent or has a low surface tension. Thus improves wetting of drug particles
by decreasing interfacial tension between dissolution medium and tablet
surface.25 With the liquisolid technology, a liquid may be transformed into a
free flowing, readily compressible and apparently dry powder by simple physical
blending with selected excipients named the carrier and coating material. The
liquid portion, which can be a liquid drug, a drug suspension or a drug
solution in suitable non-volatile liquid vehicles, is incorporated into the
porous carrier material Fig. 2.26
Figure 2: Schematic representation of
liquisolid systems
Mathematical model of Liquid solid Systems:
The
mathematical model given by Spireas et Al is used as formulation design model
for the liquisolid tablets. This approach is based on the flowable
(Ф-value) and compressible (Ψ-number) liquid retention potential
introducing constants for each powder/liquid combination.
The
Ф-value is defined as the maximum weight of liquid that can be retained
per unit weight of powder material in order to produce an acceptably flowing
liquid/powder admixture.
The
Ψ-value is defined as the maximum weight of liquid that can be retained
per unit weight of the powder material in order to produce an acceptably
compressible liquid or powder admixture i.e. being able to yield tablets of
satisfactory mechanical strength without presenting any liquid squeezing out of
liquisolid mass during compression. The excipients ratio (R) or the carrier:coating material
ratio is represented as follows:
R = Q / q--------
(1)
Where,
R is ratio of carrier (Q) and coating materials (q). For, a successful
formulation design, this ratio R should be suitably selected. Depending on the
excipient ratio (R) of the powder substrate an acceptably flowing and
compressible liquisolid system can be obtained only if a maximum liquid load on
the carrier material is not exceeded. This liquid/carrier ratio is termed
“liquid load factor Lf [w/w] and is defined as the weight ratio of the liquid
formulation (W) and the carrier material (Q) in the system:
Lf = W/Q-------- (2)
R
represents the ratio between the weights of the carrier (Q) and the coating (q)
material present in the formulation. The liquid load factor that ensures acceptable flowability
(Lf) can be determined by:
Lf =Φ+ φ.
(1/R) -------- (3)
Where
Φ and φ are the Ф-values of the carrier and coating material,
respectively. Similarly, the liquid load factor for production of liquisolid systems with acceptable
compactability (ΨLf) can be determined by:
Ψ Lf = Ψ + ψ (1/R)----- (4)
Where
Ψ and ψ are the Ψ-numbers of the carrier and coating material,
respectively.27-28
Mechanisms
of enhanced drug release from liquisolid systems:
Several mechanisms of enhanced drug release have been postulated for
liquisolid systems. The three main suggested mechanisms include an increased
surface area of drug available for release, an increased aqueous solubility of
the drug, and an improved wettability of the drug particles. Formation of a
complex between the drug and excipients or any changes in crystallinity of the
drug could be ruled out using DSC and XRPD measurements.29
Increased drug surface area:
If the drug within the liquisolid system is completely dissolved in the
liquid vehicle it is located in the powder substrate still in a solubilized,
molecularly dispersed state. Therefore, the surface area of drug available for
release is much greater than that of drug particles within directly compressed
tablets.30
Increased aqueous solubility of the drug:
In addition to the first mechanism of drug release enhancement it is
expected that Cs, the solubility of the drug, might be increased with
liquisolid systems. In fact, the relatively small amount of liquid vehicle in a
liquisolid compact is not sufficient to increase the overall solubility of the
drug in the aqueous dissolution medium. However, at the solid/liquid interface
between an individual liquisolid primary particle and the release medium it is
possible that in this microenvironment the amount of liquid vehicle diffusing
out of a single liquisolid particle together with the drug molecules might be
sufficient to increase the aqueous solubility of the drug if the liquid vehicle
acts as a cosolvent.30
Improved wetting properties:
Due
to the fact that the liquid vehicle can either act as surface active agent or
has a low surface tension, wetting of the liquisolid primary particles is
improved . Wettability of these systems has been demonstrated by measurement of
contact angles and water rising times.31
Components of Liquisolid Compact
Formulation:
Liquisolid compact mainly
includes
1. Non volatile solvent
2. Disintegrant
3. Carrier material
4. Coating material
1. Non volatile Solvent:
Non volatile Solvent should be
Inert, high boiling point, preferably water-miscible and not highly viscous
organic solvent systems and compatible with having ability to solubilise the
drug. The non volatile solvent acts as a binding agent in the liquisolid formulationVarious
non-volatile solvents used for the formulation of liquisolid systems include
Polyethylene glycol 200 and 400, glycerin, polysorbate 80 and propylene glycol.
2. Disintegrant:
Superdisintigrants increases the
rate of drug release, water solubility and wettability of liquisolid granules.
Mostly superdisintigrants like sodium starch glycolate and crosspovidone
3. Carrier Materials:
Carrier material should be
porous material possessing sufficient absorption properties which contributes
in liquid absorption.The carrier and coating materials can retain only certain
amounts of liquid and at the same time maintain acceptable flow and compression
properties hence, increasing moisture content of carrier’s results in decreased
powder flowability These include grades of microcrystalline cellulose such as
avicel PH 102, avicel PH 200 ,20.
4. Coating Materials:
Coating material should be a
material possessing fine and highly adsorptive particles which contributes in
covering the wet carrier particles and displaying a dry-looking powder by
adsorbing any excess liquid.Coating material is required to cover the surface
and maintain the powder flowability34.Coating material includes silica
(Cab-O-Sil) M520,35,Aerosil 20030, Syloid, 244FP 20,35 etc.32-33
Pre-formulation
studies for liquid solid compact formulation:
Before formulating the
liquisolids first perform the preformulation studies these include
1. Solubility studies
2. Angle of slide
3. Liquid load factor
4. Pre-compression studies
Solubility studies:
Spectroscopic method:
It includes determination of
solubility of drug in different non-volatile solvents by preparing saturated
solutions. Saturated solutions are prepared by adding excess amount of drug to
the solvent and placed in orbital shaker for 48hr at 250c. Then the solutions
were filtered, diluted and analyzed by U.V spectrophotometer.
Synthetic method for
determination of solubility:
In this method 1-40mg of sample
(drug) was taken in screw cap vials to which incremental amounts of solvent is
added and was shaken for two minutes after each addition of solvent in vial
shaker until clear solution is formed.34 Determined the solubility
of the sample by using the following formula
Solubility = Volume of
solvent added (ml)
Amount
of drug taken (mg)
Angle of slide:
The required amount of carrier
material is weighed and placed on a slide and gradually raise the slide till
the slide is angular to the horizontal. The angle at which carrier slides from
the slide is measured as angle of slide. It is used to measure the flow
properties of powders. The 330 is optimum for flow of powders.35
Determination of flowable liquid
retention potential (Φ value):
The
appropriate amounts of carrier and coating materials to produce acceptable
flowing and compactible powders are based on the physical properties of powders
termed ‘‘flowable liquid-retention potential” (Ø -value). Here increasing
amounts of liquid paraffin is added to a powdered material and mixed well. The
powder absorbs or adsorbs only the liquid paraffin giving a change in flow
properties. At each concentration of the liquid paraffin added, the angle of
slide is redetermined according to previously described procedure. The Ø values
are calculated according to equation:
Ø value = weight of liquid /
weight of solid.
Calculation of liquid load
factor (Lf):
An
acceptably flowing and compressible liquisolid system can be prepared only if a
maximum liquid on the carrier material is not exceeded; such a characteristic
amount of liquid is termed the liquid load factor (Lf) Liquid load factor (Lf):
defined as weight of liquid medicament (W) to weight of carrier (Q).
Lf
= W/Q
Different
concentrations of non-volatile solvents are taken and the drug is dissolved.
Such liquid medication is added to the carrier-coating material admixture and
blended. Using above equation, drug loading factors are determined and used for
calculating the amounts of carrier and coating materials in each formulation.34
Liquid load factor (Lf):
It is defined as the ratio of
weight of liquid medication (w) to weight of carrier material (Q). It is
determined by dissolving or
dispersing the drug in nonvolatile solvent and to this carrier-coating material
admixture is added and blended. The amount of carriercoating admixture is used
to convert into free flow.36
Method of preparation of
liquisolid tablets:
Preparation of liquisolid
tablets:
Calculated quantities of drug
and non-volatile solvent is accurately weighed in 20 ml glass beaker and then
heated to dissolve the drug in that solvent. The resulting hot medication is
incorporated into calculated quantities of carrier and coating materials.
Mixing process is carried out in three steps. During the first stage, the
system is blended at an approximate mixing rate of one rotation per second for
approximately one minute in order to evenly distribute liquid medication in the
powder. In the second stage, the liquid/powder admixture is evenly spread as a
uniform layer on the surfaces of a mortar and left standing for approximately 5
min to allow drug solution to be absorbed in the interior of powder particles.
In the third stage, the powder is scraped off the mortar surfaces by means of
aluminum spatula and then blended with sodium starch glycolate for another 30
seconds in a similar way to the first stage. This gives final liquisolid
formulation to be compressed.37 The steps involved in preparation of
liquid solid complex are summarized in fig 3.38
Figure 3: Steps involved in the preparation
of liquisolid systems
Evaluation of Liquisolid Systems:
Pre compression evaluation
parameters:
Flow behavior:
Flow properties are the important
concern in the formulation and industrial production of tablet dosage form.
Angle of repose is characteristic to the flow rate of powder. In general,
values of angle of repose ≥ 40º indicate powders with poor flowability.
Differential Scanning
Calorimetry (DSC):
It is necessary to determine any
possible interaction between excipients used in the formulation. This
will also indicate success of stability studies. If the characteristic peak for
the drug is absent in the DSC thermogram, there is an indication that the drug
is in form of solution in liquisolid formulation, hence it is
molecularly dispersed within the system.
X-ray diffraction (XRD):
Generally, disappearance of
characteristic peaks of drug in the liquisolid formulation and retaining peaks
of carrier material is observed30. This indicates that drug gets converted to
amorphous form or in solubilized form in the liquisolid formulation.
Scanning Electron Microscopy
(SEM):
After SEM study, complete
disappearance of crystals of drug which confirms that drug is totally
solubilized in liquisolid system and this ensures the complete solubility.
Fourier Transform Infrared spectroscopy
(FTIR) (Bhise et al., 2009):
FTIR studies are performed to determine the
chemical interaction between the drug and excipients used in the formulation.
The presence of drug peaks in the formulation and absence of extra peaks
indicates there is no chemical interaction.39
Post compression Evaluations :
a) Content of uniformity
b) Hardness
c) Weight variation
d) Friability
e) Disintegration
f) In - vitro dissolution studies
These are should be in the
official limits prescribed by official pharmacopoeia.40
Stability of liquisolid systems with enhanced drug
release:
To obtain information on the stability of liquisolid systems, the
effects of storage on the release profile and the crushing strength of
liquisolid compacts were investigated. Stability studies of liquisolid systems
containing polythiazide (40 °C/ 42 and 75 % R.H., 12 weeks)41,
hydrocortisone (ambient conditions, 10 months), carbamazepine (25 °C/ 75 %
R.H., 6 months)42, indomethacin (25 °C/ 75 % R.H., 12 months)43,
piroxicam (25 °C/ 75 % R.H., 6 and 9 months, respectively)44, or
naproxen (20 °C/ 76 % R.H., 4 weeks)45 showed that storage at
different conditions neither had an effect on the hardness nor on the release
profiles of liquisolid compacts. This indicates that the technology is a
promising technique to enhance the release rate without having any physical
stability issues.
In vivo evaluation of immediate release liquisolid
systems:
The liquisolid technology is a promising approach for the enhancement of
drug release of poorly soluble drugs. The absorption characteristics of
hydrochlorothiazide liquisolid compacts in comparison with commercial tablets
were studies in beagle dogs.46 Significant differences in the area
under the plasma concentration-time curve, the peak plasma concentration, and
the absolute bioavailability of the liquisolid and the commercial tablets were
observed. However, for the mean residence time, the mean absorption time, and
the rate of absorption no significant differences were found. The absolute
bioavailability of the drug from liquisolid compacts was 15 % higher than that
from the commercial formulation.
The in vitro and in vivo performance of famotidine liquisolid compacts
were investigated in comparison with directly compressed tablets and commercial
famotidine tablets, respectively.47 The dissolution rate of
famotidine in 0.1 N HCl was shown to be enhanced with the liquisolid compacts
compared to directly compressed tablets. The in vivo evaluation of famotidine
liquisolid compacts was compared to that of commercial famotidine tablets using
six healthy male volunteers aged between 20 and 40. It was found that there
were no significant differences between the mean peak plasma concentrations
(cmax), the mean times of peak plasma concentrations (tmax), or the mean area
under the plasma concentration-time curve (AUC). Unfortunately, the in vivo
evaluation of the directly compressed tablets was not determined in this study
and thus, an improved bioavailability of liquisolid compacts compared to
directly compressed tablets could not be shown. The poorly soluble
antiepileptic drug carbamazepine drug release was measured from liquisolid
compacts and commercial tablets.48 It was observed that drug release
from liquisolid compacts and that from commercial tablets is comparable.
Furthermore, an oral dose of carbamazepine administered to mice led to less
protection against an electroshock-induced convulsion with liquisolid compacts
compared to the commercial product. This lower pharmacological activity of
liquisolid compacts is probably due to the high drug concentration in the
liquid vehicle and thus a precipitation of carbamazepine in the silica pores.
The bioavailability and
biological activity (glucose tolerance in rabbits) of repaglinide formulated as
liquisolid compacts and commercial tablets were investigated respectively.49
It was found that the relative bioavailability of repaglinide from the
liquisolid compacts was significantly higher than that from the commercial
tablets. The increase in insulin blood level was more pronounced with the
liquisolid compacts than with the commercial tablets indicating a higher
bioavailability from the liquisolid compacts. Moreover, liquisolid compacts of
repaglinide decreased blood glucose levels significantly more than the
commercial tablets. These partially contrary results of bioavailability of
liquisolid formulations show that still more in vivo data is needed to confirm
the superiority of liquisolid compacts.
CONCLUSION:
This Liquisolid technique gives
a design to enhance the absorption as well as dissolution rate their by it may
enhance the bio availability of a poorly soluble, insoluble or lipophilic drug
and to formulate them into immediate release or else sustain release by
selection of suitable solvent and carrier. In this technique drug is dissolved
in a non volatile solvent and their by this liquid medicament is converted to
non adherent, dry looking and free flowing by using suitable carrier and
coating material. Because of the presence of drug in the state of solubilised
or moleculary dispersed state, so solubility of insoluble drug is enhanced.
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