Abstract:
The term ‘solubility’ is defined as an excess amount of solute that can be
incorporated in a given amount of solvent. Solubility of poorly water-soluble drugs is
one of the most emerging issue associated with these drugs to form a suitable dosage
form that will provide desired pharmacological response. Their low solubility causes
elimination of most of the drug from body as such, and desired therapeutic levels are not
achieved. In recent years, a large number of drugs have been developed, but nearly 70%
of new drugs have poor water solubility. Major part of the human body is made up of
water. Therefore, drugs must be having a certain aqueous solubility. The solubility of
drugs ultimately has strong impact on their bioavailability. Rosuvastatin calcium (RST)
belongs to the Biopharmaceutics Classification System class II having low solubility and
high permeability. It is a poorly water-soluble 3-hydroxy-3-methyl glutaryl CoA (HMG-
CoA) reductase inhibitor.
Efforts have been made to enhance solubility of these drugs. Different techniques
have been used to enhance solubility of these poorly water soluble drugs such as
reduction in particle size to increase surface area, thus increasing the dissolution rate of
drug, solubilization in surfactant systems, formation of water-soluble complexes, drug
derivatization such as strong electrolyte salt forms that usually have higher dissolution
rate, producing liquisolid formulations, manipulation of the solid state of a drug
substance to enhance drug dissolution i.e. by decreasing crystallinity of the drug
substance through formation of solid solutions, solid dispersion formulations.
Polymers are major players in these formulations to enhance solubility e.g.,
chitosan, polyvinyl pyrolidone, polyvinyl alcohol, β-cyclodextrin, etc. β-Cyclodextrin is
one of the most efficient polymer among all of these to work as a carrier for these drugs
to enhance solubility.
In present work, fast disintegrating tablets (FDT’s) of rosuvastatin calcium were
prepared by using β-cyclodextrin as polymer along with different super disintegrants such
as kyron T 134 and sodium starch glycolate and microparticles were prepared by using β-
cyclodextrin as polymer to enhance solubility. Microparticles were prepared by using
solvent evaporation (solid dispersions), kneeding technique (inclusion complexes) and
XXIfree radical polymerization to prepare hydrogel microparticles. Prepared formulations
were evaluated by Fourier Transform Infrared Spectroscopy (FTIR), Differential
Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA), dissolution studies,
powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), zeta size and
zeta potential, transmission electron microscopy (TEM), and stability studies to confirm
enhancement in solubility. FDT’s were further characterized by wetting time, wetting
volume, disintegration time, dispersion time etc. Different in vitro kinetic models such as
zero order, first order, Higuchi, and Korsmeyer–Peppas were applied to determine the
release behavior of drug from prepared formulations. Results were also statistically
analyzed by mean, one-way analysis of variance (ANOVA), and p value was determined
to check significant results.
Results of FTIR and DSC of prepared formulations had revealed that stable
complex was formed between drug and polymer. SEM study of formulations had shown
that small openings were present on their surfaces. These openings facilitated the
penetration of water and rapid release of drug. From PXRD study it was observed that
drug had changed from crystalline to amorphous form. Internal morphology of TEM
images had shown that drug was present inside of FDT’s and microparticles. Zeta size
and zeta potential studies confirmed that microparticles had micron size and net charge
was neutral. Wetting time, wetting volume, disintegration time, dispersion time, water
absorption ratio of FDT’s were 43±1.15-96±1.5 seconds, 80±0.5-22±1.50 seconds,
3±1.50-77±1.50
seconds,
29±0.58-57±0.58
seconds
and
1.10±0.01-2.00±0.02,
respectively.
FDT’s and microparticles dissolution studies had shown that FDT’s released 91-
97% (p=0.025) of drug while inclusion complexes and solid dispersions released 71-92%
(p=0.15) of drug and hydrogel microparticles released upto 92% of drug (p=0.02). In
contrast to prepared formulations, drug released from commercially available tablets of
Rosuvastatin calcium was very less (43%). Due to acidic nature of Rosuvastatin calcium
drug was more soluble at higher pH value i.e., at 6.8 as compared to 1.2 pH. Hydrogel
microparticles containing Acrylamido-2-methyl propane sulphonic acid (AMPS) as
monomer had shown pH independent swelling and shown better release than methacrylic
acid
(MAA)
containing
hydrogel
microparticles.
AMPS
containing
hydrogel
microparticles released drug at both pH values but it was better at 6.8 than 1.2.
Solubility studies revealed that prepared formulations had greater solubility at 6.8
pH phosphate buffer, 1.2 pH HCl buffer and in pure water than alone drug. All three
types of formulations had enhanced solubility of Rosuvastatin calcium but it was highest
at 6.8 pH phosphate buffer. FDT’s enhanced solubility of Rosuvastatin calcium 7.42
folds in HCl buffer of 1.2 pH, while in phosphate buffer of 6.8 pH 11.71 folds and in pure
water 9.05 folds solubility was enhanced. Microparticles prepared by solvent evaporation
had enhanced solubility 3.32 folds, 8.54 folds and 5.86 folds at 1.2 pH, 6.8 pH and in
pure water, respectively. Hydrogel microparticles prepared by AMPS had enhanced
solubility 7.53 folds, 10.66 folds and 7.30 folds at 1.2 pH, 6.8 pH and in pure water,
respectively. In case of hydrogel microparticles containing MAA had no greater impact
on solubility of Rosuvastatin calcium (RST) at 1.2 pH, while these enhanced solubility
upto 9.59 folds and 6.9 folds at pH 6.8 and in pure water. From findings it was observed
that solubility of Rosuvastatin calcium was enhanced by using these techniques.
Pharmacokinetic data had also depicted that C max and AUC 0-24 were also greater
for prepared formulations in contrast to RST commercially available tablets. Elimination
half-life of drug was reduced upto 4 hours in our formulations. Toxicology data also
shown that no toxic effects were observed from hematological, biochemical and
histological studies.
From findings of this study it was concluded that solubility of Rosuvastatin
calcium was successfully enhanced by using techniques. Prepared formulations were
found stable during stability studies of 6 month period. Thus, we can conclude that
solubility of BCS class drugs can be enhanced by using these techniques with improved
bioavailability.