Solubility enhancement of poorly aqueous soluble novel drug using natural gum as carriers

The current article is based on the concept to enhance the solubility and dissolution rate of a model drug, Rosuvastatin Calcium, which is BCS class-II drug with anti-hyperlipidemic potential. The reported bioavailability from oral route of drug is only 20%. So aim of current study is to improve the solubility and dissolution rate of a poorly water-soluble drug Rosuvastatin Calcium, by solid dispersion technique. Physical mixtures and solid dispersions were prepared using natural polymers A. Marmelos in different to drug to carrier ratios. Prepared formulations were characterized in solid state by FTIR analysis, powder X-ray diffraction, Scanning electron microscopy and in-vitro dissolution study. Solid state characterizations indicated the Rosuvastatin Calcium was present in amorphous form and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Rosuvastatin Calcium, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. The mixtures of solid dispersion and excipients were evaluated for pre-compression parameters. After then fast dissolving tablets were prepared by direct compression technique. The formulated tablets were evaluated by post compression parameters . In-vitro drug release performance of the developed formulations was investigated.


Introduction
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the solvent used as well as on temperature and pressure. Absorption of a drug through the oral route involves its dissolution from the formulation into gastric and/ or intestinal fluids followed by its permeation through gastrointestinal cell membranes and finally into the systemic circulation. Oral solid dosage forms are one of the most commonly used formulation types having multiple benefits over other formulations/routes. However, the challenge for a pharmaceutical scientist lies in the fact that dissolution of a drug from an oral solid formulation (a key factor in drug absorption) is dependent on the aqueous solubility of the drug. Therefore, a drug with poor aqueous solubility would exhibit dissolution rate limited absorption and similarly a drug possessing poor membrane permeability undergo permeation rate limited absorption. 1

Process of solubilization
Solubilization of poorly soluble drugs is a frequently encountered challenge in screening studies of new chemical entities as well as in formulation design and development. A number of methodologies can be adapted to improve solubilization of poor water soluble drug and further to improve its bioavailability. Orally administered drugs completely absorb only when they show fair solubility in gastric medium and such drugs shows good bioavailability. Bioavailability depends on several factors, drug solubility in an aqueous environment and drug permeability through lipophillic membranes being the important ones. 2,3 Drug & excipient profile Rosuvastatin calcium is a statin having antilipidemic activity that synthetically inhibits the Hydroxymethylglutaryl-COA-reductase enzyme. Rosu cal is a noval active substance is a white yellowish powder which shows no polymorphism. It belongs to a new generation of methane-sulphonamide pyrimidine and N-methane sulfonyl pyrrole-substituted 3,5-dihydroxy-heptenoates. Most of the statin drugs lack systemic bioavailability due to their absorption profile. So in order to reach effective therapeutic concentration, large doses of drugs in frequent intervals of time are needed to be administerted; this may lead to induce adverse effects and may lack patient compliance. Gum is obtained from fruits of A. marmelos belonging to family Rutaceae. In many investigations high aqueous solubility of A.marmelos gum has been evaluated. Gum karaya, or sterculia gum, is the dried exudates of sterculia urens.

Objectives
The objective of this research work was to increase the solubility of the Rosuvastatin calcium by increasing its release rate with the help of various carriers and also formulating fast dissolving tablets of the prepared solid dispersion of API. The mathematical tools to be employed for the bio-statistical evaluation of the formulations.

Experimental
Preparation of Aegle Marmelos gum 1kg fruit was obtained and gum extract from fruits manually. Dried at room temperature for 3 days. After then crush in mortar and powder pass through sieve no.#85.Gum was solublised in distilled water and wash with acetone upto 150 ml. precipitation occur then filter and filtrate gum dried at 30oc for 1day. Light brown color of A.Marmelos was obtained. 4

Preparation of formulation Preparation of physical mixtures of Rosuvastatin Calcium with three different carriers
Physical mixture were prepared by mixing accurate weight of Rosuvastatin Calcium with carriers in drug to polymers ratio 1:0.50,1:0.75,1:1 (A1,B1,C1,A2,B2,C2,A3,B3,C3) respectively. The physical mixture was pulverizes and then mixed thoroughly in mortar with a pestle until homogenous mixture was obtained. The mixture was passed through sieve no. #85 collected and stored in close container away from humidity until use.

Preparation of solid dispersion of Rosuvastatin Calcium with polymers
Solid dispersions of Rosuvastatin Calcium with polymers were prepared by the solvent evaporation method. In-vitro dissolution studies of rosuvastatin calcium, physical mixtures and solid dispersions Rosuvastatin Calcium, physical mixtures and solid dispersion equivalent to 100 mg of Rosuvastatin Calcium were used for studying the rate and extent of drug dissolution. The study was performed using USP Type II (Paddle type).

Formulation of fast dissloving tablets of rosuvastatin calcium
Direct compression method was used to prepare 10mg dose strength Rosuvastatin Calcium fast dissolving tablets. The materials were accurately weighed and mixed together to obtain homogeneous or uniform mass mixture which was sieved through mesh size #42. Sodium Starch Glycolate (SSG) was used as superdisintegrant. Micro-crystalline cellulose (MCC) was used as directly compressible material 5 and magnesium stearate was used as tablet lubricant. Talc as glident or anticaking agent.

pre-formulation studies Physical Appearance
Rosuvastatin Calcium is a yellowish white powder with crystalline nature Melting point Melting point of the drug was found to be 119ºC which is agreement with the reported value (122ºC) Analytical Study

Determination of absorbance of Rosuvastatin Calcium
Rosuvastatin Calcium was estimated at UV-maxima of 243.2 nm in water+methanol, pH 6.8 & pH 7.4 phosphate buffers using UV-Visible double beam spectrophotometer. The scanning of the drug was done in the range of nm as shown in figure.

Interday and Intraday precision
Interday precision was found to be in the range of 0.1-0.6 and intraday precision was found to be 0.09 to 0.6

Repeatability
The repeatability mean concentration was found to be 0.693 µg/ml

Drug dontent
The uniformity in the drug content 11 for all the formulations was found to be within the limits of 90-100% and results are shown in Table 9.

In -vitro dissolution studies
The in vitro release profile of Rosuvastatin Calcium in pH 6.8 phosphate buffer is shown in figure.

Scanning electron microscopy
The SEM images of Rosuvastatin Calcium, Physical Mixture and the solid dispersion are shown in below.

Fast dissolving tablets of rosuvastatin calcium
Fast dissolving tablets of Rosuvastatin Calcium was prepared using different excipients i.e., superdisintegrants, binders, lubricants and ten evaluated for various parameters to select the best combination to prepare Rosuvastatin Calcium tablets. Superdisintegrants play important role in case of fast dissolving tablets as they subject the tablet disintegrate in proper time to get its effect. The incorporation of superdisintegrant in the solid dispersion tablets can also strongly enhance the dissolution rate of the lipophillic drug. From the dissolution profile of solid dispersion it was concluded that the SD9 show maximum cumulative drug release in 1 hour. So the SD9 was selected for the preparation of fast dissolving tablets. Different trials were taken to formulate an optimized formulation with sufficient mechanical strength, disintegration time and dissolution profile. Table 7 shows the different trials, which were undertaken for formulating FDTs. [22][23]  For the preparation of Fast Dissolving Tablets of Rosuvastatin Calcium, various excipients were screen for the best formulation and their concentrations were optimized thereafter. In earlier studies it was suggested that the sodium starch glycolate has positive impact on the disintegration time of solid dispersion of various poorly soluble drugs increasing their dissolution rate. So the SSG selected as superdisintegrant in the present study.
The batches F1 to F9 were prepared and the uniform mass was sieve through mesh #85. The powder mass was also evaluated for angle of repose, bulk density, tapped density, Hausner's ratio and compressibility index. After the evaluation of the powder, tablets were prepared using direct compression method. Microcrystalline cellulose was used as directly compressible material which also has disintegrant property. The prepared tablets were evaluated for hardness, uniformity of weight, thickness, wetting time, wetting ratio, disintegration time, friability, dissolution test.

Evaluation of fast dissolving tablets Pre-compression evaluations for the powder blend
Pre-compression evaluation studies were carried out to ensure the flow properties of the powder blend. Good flow properties of the powder blend will yield the tablets of desired quality and ease the tableting process. So, it was mandatory to assess the flowbility of the blend before compression. The results of pre-compression evaluation were shown in Table 8.

Post compression evaluations
The tablets obtained after compression were evaluated on various parameters to determine their quality and to ensure that the resultant product meets all necessary criteria's required for the fast dissolving tablets.

Dissolution studies
The dissolution studies were performed to evaluate the release profile of the drug, which relates the percentage of drug release from its dosage form with the function of time. The percentage cumulative release of fast dissolving tablet and marketed tablets of Rosuvastatin Calcium is shown in figure.21.   From the dissolution studies, it can be concluded that the dissolution rate of the drug of the marketed tablets was low as compared to the fast dissolving tablets of the Rosuvastatin Calcium prepared by direct compression method after the formulation of solid dispersions.      The R 2 value was found to be highest for Higuchi model i.e., 0.989 which indicates that the polymer formed a hydrophilic matrix in which drug gets entrapped in an amorphous form. As the matrix depletes, the drug in the amorphous form is available for dissolution. 25

Summary and Conclusion
Aim of the present investigation was to enhance the solubility and dissolution rate of Rosuvastatin Calcium. Solid dispersions of Rosuvastatin Calcium were prepared by using A.Marmelos, as carriers in different ratios through solvent evaporation method. On the basis of maximum percentage drug release the optimized formulation of solid dispersion of Rosuvastatin Calcium was characterized by various analytical methods. The fast dissolving tablets of the optimized solid dispersion were prepared and evaluated for various parameters. The tablets were evaluated for various pharmacopeial tests. A released kinetic data through mathematical tools indicated the drug release follow Higuchi model, which indicates that the carrier formed a hydrophilic matrix in which drug gets entrapped in an amorphous form. As the matrix depletes, the drug in the amorphous form is available for dissolution. Thus, it can be concluded that the solid dispersion technology can be used as that alternative to produced fast tablets especially for drugs having poor water solubility.