The objective of the present work was to enhance the solubility and dissolution of practically water-insoluble drug raloxifene HCl (RLX), for the same two approaches that were used. In the first approach, drug was kneaded with hydroxypropyl-
Solubility of a drug is an important property that mainly influences the extent of oral bioavailability. Enhancement of oral bioavailability of poorly water soluble drugs is the most challenging aspect of drug development [
Raloxifene (marketed as Evista by Eli Lilly and Company) is an oral second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It is 2-(4-hydroxyphenyl)-3-({4-[2-(piperidin-1-yl) ethoxy] phenyl} carbonyl)-1-benzothiophen-6-ol that has estrogenic actions on bone and antiestrogenic actions on the uterus and breast. It belongs to class II drug according to biopharmaceutical classification system (BCS), that is, low solubility and high permeability. But raloxifene has very less bioavailability, only 2%, and it would be advantageous to increase the solubility of such molecule. Raloxifene is available in salt form as raloxifene HCl [
In this study, two strategies were used, which were aimed at improving the aqueous solubility. The first one is complexation of drugs with cyclodextrin, and the second one is Cogrinding with natural polymers. Cyclodextrins (CDs) are cyclic macromolecules, obtained by the degradation of starch by
The present study was carried out to investigate the inclusion complex of raloxifene HCl and HP
Raloxifene (RLX) was obtained as a gift sample from Zydus Cadila Healthcare Ltd., Ahmedabad, India. HP
Phase solubility study of raloxifene HCl in distilled water.
Sr. no. | Formulation code | A1 | A2 | A3 | A4 |
---|---|---|---|---|---|
1 | Drug (mg) | 20 | 20 | 20 | 20 |
2 | HP |
20 | 40 | 60 | 80 |
3 | Distilled Water (mL) | 20 | 20 | 20 | 20 |
Dissolution rates from RLX, RLX-HP
All results are expressed as mean ± S.D. Differences between the two related parameters were considered statistically significant for
Cyclodextrin (CD) has a hydrophobic central cavity and hydrophilic outer surface and can encapsulate model substrates to form host-guest complexes or supramolecular species. This usually enhances drug solubility in aqueous solution and affects the chemical characteristics of the encapsulated drug. HP
The natural polymers are mainly evaluated in industry for their new applications. Due to the less toxic effect and low production cost, these polymers mainly used as drug carrier in pharmaceutical industry. Guar gum has surfactant activity [
The results of swelling index and viscosity of polymers are given in Table
Characterization of guar gum and modified guar gum. All values are mean ± S.D,
Polymer | Viscosity (cP) | Swelling index (%) |
---|---|---|
Guar gum | 323 ± 18.52 | 2905.46 ± 6.01 |
Modified guar gum | 197 ± 10.43 | 2700.69 ± 10.13 |
Optimization ratio of RLX with guar gum and modified guar gum. All values are mean ± S.D,
Ratio | Concentration (mg/mL) | |
---|---|---|
RLX-GG | RLX-MGG | |
1 : 1 | 1.11 ± 0.041* | 0.87 ± 0.065* |
1 : 2 | 1.33 ± 0.005* | 1.09 ± 0.004* |
1 : 3 | 1.40 ± 0.109* | 1.11 ± 0.010* |
1 : 4 | 1.46 ± 0.017* | 2.13 ± 0.011* |
1 : 5 | 1.63 ± 0.012* | 2.30 ± 0.031* |
1 : 6 | 2.01 ± 0.015* | 2.41 ± 0.013* |
1 : 7 | 2.18 ± 0.056* | 3.54 ± 0.011* |
1 : 8 | 2.32 ± 0.015* | 3.69 ± 0.012* |
1 : 9 | 2.35 ± 0.007 | 3.67 ± 0.023 |
*Significant (
As shown in Figure
DSC thermogram of (a) raloxifene HCl, (b) HP
As shown in Figure
PXRD of (a) raloxifene HCl, (b) HP
As shown in Figure
FTIR spectra of (a) raloxifene HCl, (b) HP
As shown in Figure
SEM of (a) raloxifene, (b) raloxifene-HP
Phase solubility diagram of raloxifene.
Solubility of RLX and cogrind mixtures in different solvent at 37 ± 0.5°C after 48 hrs. All values are mean ± S.D,
Sample | Medium | ||
---|---|---|---|
Water |
pH 1.2 HCl buffer |
pH 7 phosphate buffer | |
RLX | 0.097 ± 0.105 | 0.082 ± 0.079 | 0.076 ± 0.023 |
RLX-GG | 2.090 ± 0.002* | 2.037 ± 0.160* | 2.610 ± 0.020* |
RLX-MGG | 3.570 ± 0.27* | 3.173 ± 0.030* | 3.870 ± 0.360* |
*Significant (
Figure
Dissolution efficiency of RLX, RLX-HP
Sample | Dissolution efficiency | |
---|---|---|
DE60 | DE120 | |
Raloxifene | 28.92 ± 1.98* | 41.41 ± 2.04 |
RLX-HP |
83.34 ± 1.14* | 84.47 ± 0.84* |
RLX-MGG cogrind mixture | 49.70 ± 1.18* | 51.30 ± 1.57* |
*Significant (
Dissolution profile of RLX, RLX-HP
The molecular structure of cyclodextrin creates a bucket-like cavity that can function to complex with drug or functional groups on drug. The investigation suggests from phase solubility study and dissolution rate profile of the inclusion complex that the solubility and dissolution rate of raloxifene increases significantly due to HP
Hence, from practical point of view, Cogrinding method appeared easier and was considered as the most convenient method. But when both these techniques were compared the inclusion complex method showed better results as compared to those of the other methods and thus was found to be more effective than Cogrinding method.
The authors report no conflict of interests.
The authors are thankful to R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, for providing all the necessary facilities to carry out this research work.