Techniques to improve the solubility and flow properties

of the drug having potent clinical applications.

BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

Abstract defined as the spontaneous

The drug under study is having high
clinical applications but is facing
difficulty to be formulated into tablets
because of low solubility and flow
properties. Hence, in this study
various techniques are used such as
milling, use of co-solvents and
complexation of the drug in order to
improve the solubility and dissolution
of the drug. Approaches like ball
milling are also used to increase the
flow properties of the drug. Drug is
analyzed for the improvement and
satisfactory results are discussed. It
was inferred from the studies that PEG
4000 resulted to be helpful in
enhancing the solubility and flow
property of the drug.
Introduction
Solubility can be defined in both ways
quantitatively and qualitatively.
Quantitatively it can be defined as
concentration of solute in a saturated
solution at a certain temperature.
Moreover, qualitatively it can be
interaction of two or more substances
to form a homogeneous molecular
dispersion. The solubility of drug
molecules plays a key role in its
bioavailability. The aqueous solubility
of poorly aqueous soluble drug
molecules in the gastrointestinal fluid
often causes unsatisfactory
bioavailability. Poorly aqueous soluble
drugs often require high doses in
order to reach therapeutic plasma
concentrations after oral
administration. Compounds with
insufficient solubility carry a higher
risk of failure during discovery and
development. This happens because
achieving good activity against a
biological target is of paramount
importance and structural features
that produce good activity (e.g.
lipophilic substructures) can reduce
solubility.
Based on the Biopharmaceutics
classification system, drugs can be
classified into following categories:
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

Poor aqueous solubility is caused by

two main factors: I) high lipophilicity
II) strong intermolecular interactions
which make the solubilization of the
solid energetically costly. Ideally, the
limits for the solubility are defined as:
a compound with an average potency
of 1mg/kg should have a solubility of
at least 0.1g/L to be adequately
soluble. If a compound with the same
potency has a solubility of less than
0.01g/L it can be considered poorly
soluble. Classification of solubilities as
per Indian pharmacopeia is given as:
Solubility improvement techniques
can be categorized in to physical
modification, chemical modifications
of the drug and other techniques.
Physical Modifications: Particle size
reduction like Micronization and
nanosuspension, modification of the
crystal habit like polymorphs,
amorphous form and co-
crystallization, drug dispersion in
carriers like eutectic mixtures, solid
dispersions, solid solutions and
cryogenic techniques.
Chemical Modifications: Change of
ph, use of buffer, derivatization,
complexation, and salt formation.
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

Miscellaneous Methods: Supercritical Powder flow is a key requirement for

fluid process, use of adjuvant like
surfactant, solubilizers, co-solvency,
hydrotrophy, and novel excipients.
Milled products possess specific
physical attributes that contribute to
improved drug dissolution and
solubility. Milling reduces the size and
alters the size distribution of the drug
particles. These properties may be
measured by light scattering
techniques such as photon correlation
spectroscopy (5μm down to 0.001μm)
and laser diffraction (0.05μm–
2000μm), respectively. By virtue of
their smaller size, milled particles
possess larger specific surface area
compared to their un-milled
counterparts. Based on the Noyes–
Whitney equation, this is likely to
increase the dissolution rate of the
milled drug particles if the particles
can also be adequately wetted. Milled
particles possess higher surface free
energies and this, coupled with their
thinner diffusion boundary layers
further enhance the dissolution rate
of the milled drug substance.
pharmaceutical manufacturing
process. Tablets are often
manufactured on a rotary multi-
station tablet press by filling the tablet
die with powders or granules based on
volume. Thus, the flow of powder
from the hopper into the dies often
determines weight, hardness, and
content uniformity of tablets.
There are various methods available
to measure the powder flow. The
compendial methods include
measurement of angle of repose, bulk
density, tapped density, Carr’s
compressibility index, or Hausner
ratio.
Increasing Solubility and
powder flow through milling
Ball milling is a mechanical method
used in the preparation of solid
dispersions. Milling reduces the
particle size of the compound by using
both impact and attrition forces and
hence increases surface area which
helps in enhancing the bioavailability.
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

It is a simple process and has the Materials and method

advantage of being faster as
compared to many other methods.
Different carriers used as solid
dispersions are urea7, polyvinyl
pyrrolidine8, poly ethylene glycol9,
mannitol7, hydroxypropylmethyl
cellulose, β-cyclodextrin etc. In the
present study PEG 4000 and
Carrageenen were used as the
hydrophilic carriers. PEG produced by
polymerization of ethylene oxide
helps in improving wettability and also
forms solid drug solutions. It has low
toxicity and has the advantage of
being soluble in many organic
solvents9.
Carrageenens are obtained from a
natural source(seaweed) and are
highly flexible molecules. They are
often used as thickening and
stabilizing agents. The purpose of this
study was to analyze the effect of
milling on the solubility and flow
properties of drug under study with
polymers PEG 4000 and Carrageenen.
PEG 4000 was purchased from
(Qualigens fine Chemicals, Navi
Mumbai, India) and Carrageenen from
(HIMEDIA Laboratories Pvt ltd,
Mumbai, India). Other chemicals
obtained were Talc and Micro
crystalline cellulose from (Sd fine–
Chem limited, Mumbai, India), Sodium
starch glycolate from (LOBA chemicals
private limited) and Magnesium
stearate from (Paxmy speciality
chemicals). All chemicals and reagents
used were of analytical grade.
The Ball mill was purchased from
Khera Pvt ltd, New Delhi, India. It is
cylindrical in shape with an inner
diameter of 33.4 cm and outer
diameter of 37 cm. The height of the
mill was 17.5 cm. There are three
baffles attached inside the cylinder
with length and thickness of 17.2 cm
and 0.9 cm.
Preparation of solid dispersion
Mixture of the drug and the polymers
were weighed in three different ratios
of 1:1, 1:3 and 1:5 each and pure drug
of 1g was weighed separately and
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

mixed gently, the prepared physical and Carr’s index of the ball milled and
dispersions and pure drug were non-milled powder formulations were
further subjected to size reduction evaluated to find out the flow
with impact and attrition forces by property of the milled and non-milled
milling using a ball mill as follows. 10 solid dispersions and pure drug.
iron balls were placed in the milling
The formulas given below were used
vessel along with the physical mixture
for further calculation.
and rotated at a speed of 84 rpm for
30 min and 90 minutes respectively. Angle of repose = tan-1 (h/r)
The pure drug was also milled for the h - height of the heap, r- radius of the
same time intervals as the physical heap
dispersions, for better comparison.
Bulk density = Mass/Bulk Volume,
Batch Weight Polymer Milling
Code of weight(g) time(min) Tapped density = Mass/Tapped
drug(g) volume
DPEG1 1 1 30
DPEG2 1 3 30 Carr’s index = [(bulk volume-tapped
DPEG3 1 5 30 volume)/bulk volume] *100
DPEG4 1 1 90
DPEG5 1 3 90 The above procedure was repeated
DPEG6 1 5 90
thrice and the mean and standard
DC1 1 1 30
DC2 1 3 30 deviation was calculated and
DC3 1 5 30 tabulated.
DC4 1 1 90
DC5 1 3 90 Particle size Analysis
DC6 1 5 90
DP1 1 - 30 The ball milled dispersions of Drug
DP2 1 - 30 along with PEG and carageenen were
Where, DP-Pure Drug, DC- Drug with subjected to particle size
Carrageenan, DPEG- Drug with PEG. measurements by using a calibrated
Derived properties such as angle of compound light microscope by
repose, bulk density, tapped density microscopy technique. small amount
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University
of each of the milled powder sample
was spread over a glass slide, viewed
under a microscope (Khera
instruments Pvt ltd) with the help of
eye piece. micrometer and the size
was measured. Particle size of about
25 particles was noted and the
average particle size was calculated
using the formula:
Average particle size = size of the individual
particle/Total number of particles
Solubility studies
To detect and compare the solubility
of pure drug with the ball milled Drug
dispersions, the solubility studies
were carried out. Milled dispersions
equivalent to 1 mg of Drug was added
to 2 ml of distilled water and was
placed in a shaker for 24hrs at room
temperature. This was further
removed from the shaker and
centrifuged at 4500 rpm for 10 min at
4ᵒC using a cooling centrifuge (C 24,
Remi laboratory, India). The
supernatant was diluted and the
absorbance was analyzed using UV-Vis
Spectrophotometer (Sistronic 117) at
397 nm and concentration was
calculated using standard calibration
curve.
Result
Flow property
Angle of repose, Bulk density, Tapped
density were performed thrice and
the mean with standard deviation was
tabulated. The values show that
milled dispersions of DPEG of both 30
and 90 min have a very good flow
property. Though DC milled
dispersions also showed better flow
than pure drug, its flow was less as
compared to the DPEG milled
dispersions which might be because of
the binding nature of carrageenen
resulting in a hindrance in flow
property.
Particle size and Solubility
The average particle size of each
formulation. The particle size of pure
drug was obtained as 16.5 μm and
that of milled drug for 30 and 90 min
did not show any significant change.
This might be because of
agglomeration of the finely divided
particles resulting in adhesion of the
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

particles. The particle size of milled DPEG2 65.75 43.5

dispersions decreased with the DPEG3 46 32.5

polymer weight increase and also with DPEG4 57.5 49.5

DPEG5 59.5 41.5
increase in time of milling with 1:5
DPEG6 67.5 17.5
ratio of DPEG at 90 min showing a
DC1 65 24.5
particle size of only 17.5 μm as
DC2 77.75 25.5
compared to 1:1 ratio of 30 min,
DC3 63.25 31.5
where a particle size of 51.5 μm was
DC4 96.25 34.5
obtained. DC5 64 23.5
DC6 106.75 20.5
DP1 48.75 17.5
DP2 36.75 16.5
Solubility of Drug dispersions before
Milling
Batch code Solubility
DPEG1 40.75
DPEG2 62.5
DPEG3 53.25
DC1 49
DC2 93.25
DC3 70

Solubility Results
The solubility of ball milled solid
dispersions of Drug and the polymers
is shown in table. The 90 min milled
Where, NP=DP, NPEG=DPEG, NC=DC.
dispersions of DPEG (1:5) showed
Batch Code Solubility(µg/ml) Particle size(µm)better solubility 67.5μg/ml than that
of the pure drug which had a solubility
DPEG1 55 51.5 of 48.75 μg/ml. Milled Carrageenen
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

dispersions (DC) at 90 min showed a stoppered glass tubes. The tubes were
significant increase in solubility, maintained at 30.C and were shaken
106.75 μg/ml at 1:5 ratio as compared occasionally on a vortex mixer. A time
to pure drug and PEG 4000 SD. Milled period of 24hr was found sufficient for
and non-milled pure drug showed the attainment of equilibrium. The
similar solubility values which might saturated solution was filtered and
be because reaggregation of the analyzed for drug concentration. An
particles due to milling resulting in Ultra-violet absorption spectro-
larger size. photometric method was used to
estimate the drug concentration.
Absorbance of diluted solutions was
Increasing Solubility by using determined at 300/402 nm and the
co-solvent drug concentration was calculated
using beer-lambert law.
Materials and method
the drug was obtained from panacea
biotech pvt. Ltd., lalru, Punjab. All Result
other solvents used were of analytical solvent Solubility(µg/ml)
grade. Analytical grade acetonitrile Water 0.0137
Sodium Chloride 0.0173
was refluxed over Phosphrous Phosphate buffer 0.1052
pentoxide and distilled. Phosphate Tween 80 2.6496
buffer (0.1 M) prepared by mixing Ethyl Alcohol 5.4144
Propylene 5.8656
requisite amount of 0.2M sodium Alcohol
dihydrogen phosphate and 0.2M PEG 300 71.488
disodium hydrogen phosphate was PEG 400 73.600

used throughout.
For determining solubility od Drug,
excess of it was placed in contact with
5ml of solvent/co-solvent mixture in
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

as a co-solvent with results in higher

bio-availability but only for the
Conclusions Parentral preparations.
Milling Co-solvation can not be used for
increasing the solubility in tablet
From all the data obtained we can
formulations.
conclude that the milled dispersions
of the drug with polymers help in
increasing the solubility and flow
properties of Drug. Similarly milling References
brings about a reduction in particle  Overview of milling techniques for
size thereby increasing the surface improving the solubility of poorly
area and also helps in conversion of water-soluble drugs.
the crystalline compound to semi panelZhi HuiLohaAsim KumarSamantabPaul
crystalline or amorphous compound WanSia Heng
and hence can be used as a method  Solubility Enhancement by
for preparing solid dispersions. Cosolvency Approach
Among the 2 polymers used, PEG 4000 Amit Kumar Nayak and Prachi Prava
shows better improvement in Panigrahi
dissolution than carrageenen as there
 Comparative Evaluation of Flow for
were not much interactions between Pharmaceutical Powders and
PEG and Drug where as carrageenen Granules
formed a complex with Drug which
Rakhi B. Shah, Mobin A. Tawakkul, and
resulted in decrease in dissolution Mansoor A. Khan
rate.
 Drug Solubility: Importance and
Co-solvation Enhancement Techniques

This technique is particularly for the Ketan T. Savjani, Anuradha K. Gajjar, and
Parentral formulations. Hence PEG Jignasa K. Savjani
can be used to increase the solubility
Techniques to improve the solubility and flow properties
of the drug having potent clinical applications.
BY: Jay Shah(16bph030) and Submitted to: Dr. Mohit Shah
Institute of Pharmacy, Nirma University

 Effect of Ball Milling on the Physical

Dispersions for Solubility
Enhancement.
Akhila Sravya Dantu, Ramya Devi D, Vedha
Hari B.N
 Solubilization; Use of co-solvents.
January 2003Indian Journal of
Pharmaceutical Sciences 65(1):58-61
Neelam SeedherNeelam SeedherJ. Kaur.